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Bortezomib Treatment Modulates Autophagy in Multiple Myeloma

Identifieur interne : 000670 ( Pmc/Corpus ); précédent : 000669; suivant : 000671

Bortezomib Treatment Modulates Autophagy in Multiple Myeloma

Auteurs : Giuseppe Di Lernia ; Patrizia Leone ; Antonio Giovanni Solimando ; Alessio Buonavoglia ; Ilaria Saltarella ; Roberto Ria ; Paolo Ditonno ; Nicola Silvestris ; Lucilla Crudele ; Angelo Vacca ; Vito Racanelli

Source :

RBID : PMC:7073518

Abstract

Although the introduction of bortezomib as a therapeutic strategy has improved the overall survival of multiple myeloma (MM) patients, 15–20% of high-risk patients do not respond to bortezomib over time or become resistant to treatment. Therefore, the development of new therapeutic strategies, such as combination therapies, is urgently needed. Methods: Given that bortezomib resistance may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation, and that an enormous amounts of misfolded protein is generated in myeloma plasma cells (PCs), we investigated the effect of the simultaneous inhibition of proteasome by bortezomib and autophagy by hydroxychloroquine (HCQ) treatment on PCs and endothelial cells (ECs) isolated from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM. Results: We found that bortezomib combined with HCQ induces synergistic cytotoxicity in myeloma PCs whereas this effect is lost on ECs. Levels of microtubule-associated protein light chain beta (LC3B) and p62 are differentially modulated in PCs and ECs, with effects on cell viability and proliferation. Conclusions: Our results suggest that treatment with bortezomib and HCQ should be associated with an anti-angiogenic drug to prevent the pro-angiogenic effect of bortezomib, the proliferation of a small residual tumor PC clone, and thus the relapse.


Url:
DOI: 10.3390/jcm9020552
PubMed: 32085480
PubMed Central: 7073518

Links to Exploration step

PMC:7073518

Le document en format XML

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<name sortKey="Buonavoglia, Alessio" sort="Buonavoglia, Alessio" uniqKey="Buonavoglia A" first="Alessio" last="Buonavoglia">Alessio Buonavoglia</name>
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<name sortKey="Saltarella, Ilaria" sort="Saltarella, Ilaria" uniqKey="Saltarella I" first="Ilaria" last="Saltarella">Ilaria Saltarella</name>
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<nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;
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(G.D.L.);
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<name sortKey="Silvestris, Nicola" sort="Silvestris, Nicola" uniqKey="Silvestris N" first="Nicola" last="Silvestris">Nicola Silvestris</name>
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<nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;
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(G.D.L.);
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<nlm:aff id="af2-jcm-09-00552">IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;
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</affiliation>
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<name sortKey="Crudele, Lucilla" sort="Crudele, Lucilla" uniqKey="Crudele L" first="Lucilla" last="Crudele">Lucilla Crudele</name>
<affiliation>
<nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;
<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);
<email>patrizia.leone@uniba.it</email>
(P.L.);
<email>antoniogiovannisolimando@gmail.com</email>
(A.G.S.);
<email>alessio.buonavoglia85@gmail.com</email>
(A.B.);
<email>ilaria.saltarella@libero.it</email>
(I.S.);
<email>roberto.ria@uniba.it</email>
(R.R.);
<email>n.silvestris@oncologico.bari.it</email>
(N.S.);
<email>lucillacrudele@gmail.com</email>
(L.C.);
<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Vacca, Angelo" sort="Vacca, Angelo" uniqKey="Vacca A" first="Angelo" last="Vacca">Angelo Vacca</name>
<affiliation>
<nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;
<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);
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(P.L.);
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<name sortKey="Racanelli, Vito" sort="Racanelli, Vito" uniqKey="Racanelli V" first="Vito" last="Racanelli">Vito Racanelli</name>
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<nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;
<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);
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(P.L.);
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<title xml:lang="en" level="a" type="main">Bortezomib Treatment Modulates Autophagy in Multiple Myeloma</title>
<author>
<name sortKey="Di Lernia, Giuseppe" sort="Di Lernia, Giuseppe" uniqKey="Di Lernia G" first="Giuseppe" last="Di Lernia">Giuseppe Di Lernia</name>
<affiliation>
<nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;
<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);
<email>patrizia.leone@uniba.it</email>
(P.L.);
<email>antoniogiovannisolimando@gmail.com</email>
(A.G.S.);
<email>alessio.buonavoglia85@gmail.com</email>
(A.B.);
<email>ilaria.saltarella@libero.it</email>
(I.S.);
<email>roberto.ria@uniba.it</email>
(R.R.);
<email>n.silvestris@oncologico.bari.it</email>
(N.S.);
<email>lucillacrudele@gmail.com</email>
(L.C.);
<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Leone, Patrizia" sort="Leone, Patrizia" uniqKey="Leone P" first="Patrizia" last="Leone">Patrizia Leone</name>
<affiliation>
<nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;
<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);
<email>patrizia.leone@uniba.it</email>
(P.L.);
<email>antoniogiovannisolimando@gmail.com</email>
(A.G.S.);
<email>alessio.buonavoglia85@gmail.com</email>
(A.B.);
<email>ilaria.saltarella@libero.it</email>
(I.S.);
<email>roberto.ria@uniba.it</email>
(R.R.);
<email>n.silvestris@oncologico.bari.it</email>
(N.S.);
<email>lucillacrudele@gmail.com</email>
(L.C.);
<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Solimando, Antonio Giovanni" sort="Solimando, Antonio Giovanni" uniqKey="Solimando A" first="Antonio Giovanni" last="Solimando">Antonio Giovanni Solimando</name>
<affiliation>
<nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;
<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);
<email>patrizia.leone@uniba.it</email>
(P.L.);
<email>antoniogiovannisolimando@gmail.com</email>
(A.G.S.);
<email>alessio.buonavoglia85@gmail.com</email>
(A.B.);
<email>ilaria.saltarella@libero.it</email>
(I.S.);
<email>roberto.ria@uniba.it</email>
(R.R.);
<email>n.silvestris@oncologico.bari.it</email>
(N.S.);
<email>lucillacrudele@gmail.com</email>
(L.C.);
<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="af2-jcm-09-00552">IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;
<email>paolo.ditonno@fastwebnet.it</email>
</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Buonavoglia, Alessio" sort="Buonavoglia, Alessio" uniqKey="Buonavoglia A" first="Alessio" last="Buonavoglia">Alessio Buonavoglia</name>
<affiliation>
<nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;
<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);
<email>patrizia.leone@uniba.it</email>
(P.L.);
<email>antoniogiovannisolimando@gmail.com</email>
(A.G.S.);
<email>alessio.buonavoglia85@gmail.com</email>
(A.B.);
<email>ilaria.saltarella@libero.it</email>
(I.S.);
<email>roberto.ria@uniba.it</email>
(R.R.);
<email>n.silvestris@oncologico.bari.it</email>
(N.S.);
<email>lucillacrudele@gmail.com</email>
(L.C.);
<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Saltarella, Ilaria" sort="Saltarella, Ilaria" uniqKey="Saltarella I" first="Ilaria" last="Saltarella">Ilaria Saltarella</name>
<affiliation>
<nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;
<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);
<email>patrizia.leone@uniba.it</email>
(P.L.);
<email>antoniogiovannisolimando@gmail.com</email>
(A.G.S.);
<email>alessio.buonavoglia85@gmail.com</email>
(A.B.);
<email>ilaria.saltarella@libero.it</email>
(I.S.);
<email>roberto.ria@uniba.it</email>
(R.R.);
<email>n.silvestris@oncologico.bari.it</email>
(N.S.);
<email>lucillacrudele@gmail.com</email>
(L.C.);
<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Ria, Roberto" sort="Ria, Roberto" uniqKey="Ria R" first="Roberto" last="Ria">Roberto Ria</name>
<affiliation>
<nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;
<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);
<email>patrizia.leone@uniba.it</email>
(P.L.);
<email>antoniogiovannisolimando@gmail.com</email>
(A.G.S.);
<email>alessio.buonavoglia85@gmail.com</email>
(A.B.);
<email>ilaria.saltarella@libero.it</email>
(I.S.);
<email>roberto.ria@uniba.it</email>
(R.R.);
<email>n.silvestris@oncologico.bari.it</email>
(N.S.);
<email>lucillacrudele@gmail.com</email>
(L.C.);
<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Ditonno, Paolo" sort="Ditonno, Paolo" uniqKey="Ditonno P" first="Paolo" last="Ditonno">Paolo Ditonno</name>
<affiliation>
<nlm:aff id="af2-jcm-09-00552">IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;
<email>paolo.ditonno@fastwebnet.it</email>
</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Silvestris, Nicola" sort="Silvestris, Nicola" uniqKey="Silvestris N" first="Nicola" last="Silvestris">Nicola Silvestris</name>
<affiliation>
<nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;
<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);
<email>patrizia.leone@uniba.it</email>
(P.L.);
<email>antoniogiovannisolimando@gmail.com</email>
(A.G.S.);
<email>alessio.buonavoglia85@gmail.com</email>
(A.B.);
<email>ilaria.saltarella@libero.it</email>
(I.S.);
<email>roberto.ria@uniba.it</email>
(R.R.);
<email>n.silvestris@oncologico.bari.it</email>
(N.S.);
<email>lucillacrudele@gmail.com</email>
(L.C.);
<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="af2-jcm-09-00552">IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;
<email>paolo.ditonno@fastwebnet.it</email>
</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Crudele, Lucilla" sort="Crudele, Lucilla" uniqKey="Crudele L" first="Lucilla" last="Crudele">Lucilla Crudele</name>
<affiliation>
<nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;
<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);
<email>patrizia.leone@uniba.it</email>
(P.L.);
<email>antoniogiovannisolimando@gmail.com</email>
(A.G.S.);
<email>alessio.buonavoglia85@gmail.com</email>
(A.B.);
<email>ilaria.saltarella@libero.it</email>
(I.S.);
<email>roberto.ria@uniba.it</email>
(R.R.);
<email>n.silvestris@oncologico.bari.it</email>
(N.S.);
<email>lucillacrudele@gmail.com</email>
(L.C.);
<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Vacca, Angelo" sort="Vacca, Angelo" uniqKey="Vacca A" first="Angelo" last="Vacca">Angelo Vacca</name>
<affiliation>
<nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;
<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);
<email>patrizia.leone@uniba.it</email>
(P.L.);
<email>antoniogiovannisolimando@gmail.com</email>
(A.G.S.);
<email>alessio.buonavoglia85@gmail.com</email>
(A.B.);
<email>ilaria.saltarella@libero.it</email>
(I.S.);
<email>roberto.ria@uniba.it</email>
(R.R.);
<email>n.silvestris@oncologico.bari.it</email>
(N.S.);
<email>lucillacrudele@gmail.com</email>
(L.C.);
<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Racanelli, Vito" sort="Racanelli, Vito" uniqKey="Racanelli V" first="Vito" last="Racanelli">Vito Racanelli</name>
<affiliation>
<nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;
<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);
<email>patrizia.leone@uniba.it</email>
(P.L.);
<email>antoniogiovannisolimando@gmail.com</email>
(A.G.S.);
<email>alessio.buonavoglia85@gmail.com</email>
(A.B.);
<email>ilaria.saltarella@libero.it</email>
(I.S.);
<email>roberto.ria@uniba.it</email>
(R.R.);
<email>n.silvestris@oncologico.bari.it</email>
(N.S.);
<email>lucillacrudele@gmail.com</email>
(L.C.);
<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Journal of Clinical Medicine</title>
<idno type="eISSN">2077-0383</idno>
<imprint>
<date when="2020">2020</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<p>Although the introduction of bortezomib as a therapeutic strategy has improved the overall survival of multiple myeloma (MM) patients, 15–20% of high-risk patients do not respond to bortezomib over time or become resistant to treatment. Therefore, the development of new therapeutic strategies, such as combination therapies, is urgently needed. Methods: Given that bortezomib resistance may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation, and that an enormous amounts of misfolded protein is generated in myeloma plasma cells (PCs), we investigated the effect of the simultaneous inhibition of proteasome by bortezomib and autophagy by hydroxychloroquine (HCQ) treatment on PCs and endothelial cells (ECs) isolated from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM. Results: We found that bortezomib combined with HCQ induces synergistic cytotoxicity in myeloma PCs whereas this effect is lost on ECs. Levels of microtubule-associated protein light chain beta (LC3B) and p62 are differentially modulated in PCs and ECs, with effects on cell viability and proliferation. Conclusions: Our results suggest that treatment with bortezomib and HCQ should be associated with an anti-angiogenic drug to prevent the pro-angiogenic effect of bortezomib, the proliferation of a small residual tumor PC clone, and thus the relapse.</p>
</div>
</front>
<back>
<div1 type="bibliography">
<listBibl>
<biblStruct>
<analytic>
<author>
<name sortKey="Kyle, R A" uniqKey="Kyle R">R.A. Kyle</name>
</author>
<author>
<name sortKey="Rajkumar, S V" uniqKey="Rajkumar S">S.V. Rajkumar</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Siegel, R L" uniqKey="Siegel R">R.L. Siegel</name>
</author>
<author>
<name sortKey="Miller, K D" uniqKey="Miller K">K.D. Miller</name>
</author>
<author>
<name sortKey="Jemal, A" uniqKey="Jemal A">A. Jemal</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Laubach, J P" uniqKey="Laubach J">J.P. Laubach</name>
</author>
<author>
<name sortKey="Voorhees, P M" uniqKey="Voorhees P">P.M. Voorhees</name>
</author>
<author>
<name sortKey="Hassoun, H" uniqKey="Hassoun H">H. Hassoun</name>
</author>
<author>
<name sortKey="Jakubowiak, A" uniqKey="Jakubowiak A">A. Jakubowiak</name>
</author>
<author>
<name sortKey="Lonial, S" uniqKey="Lonial S">S. Lonial</name>
</author>
<author>
<name sortKey="Richardson, P G" uniqKey="Richardson P">P.G. Richardson</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Yang, W C" uniqKey="Yang W">W.C. Yang</name>
</author>
<author>
<name sortKey="Lin, S F" uniqKey="Lin S">S.F. Lin</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Harousseau, J L" uniqKey="Harousseau J">J.L. Harousseau</name>
</author>
<author>
<name sortKey="Attal, M" uniqKey="Attal M">M. Attal</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Laubach, J" uniqKey="Laubach J">J. Laubach</name>
</author>
<author>
<name sortKey="Garderet, L" uniqKey="Garderet L">L. Garderet</name>
</author>
<author>
<name sortKey="Mahindra, A" uniqKey="Mahindra A">A. Mahindra</name>
</author>
<author>
<name sortKey="Gahrton, G" uniqKey="Gahrton G">G. Gahrton</name>
</author>
<author>
<name sortKey="Caers, J" uniqKey="Caers J">J. Caers</name>
</author>
<author>
<name sortKey="Sezer, O" uniqKey="Sezer O">O. Sezer</name>
</author>
<author>
<name sortKey="Voorhees, P" uniqKey="Voorhees P">P. Voorhees</name>
</author>
<author>
<name sortKey="Leleu, X" uniqKey="Leleu X">X. Leleu</name>
</author>
<author>
<name sortKey="Johnsen, H E" uniqKey="Johnsen H">H.E. Johnsen</name>
</author>
<author>
<name sortKey="Streetly, M" uniqKey="Streetly M">M. Streetly</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Adams, J" uniqKey="Adams J">J. Adams</name>
</author>
<author>
<name sortKey="Palombella, V J" uniqKey="Palombella V">V.J. Palombella</name>
</author>
<author>
<name sortKey="Sausville, E A" uniqKey="Sausville E">E.A. Sausville</name>
</author>
<author>
<name sortKey="Johnson, J" uniqKey="Johnson J">J. Johnson</name>
</author>
<author>
<name sortKey="Destree, A" uniqKey="Destree A">A. Destree</name>
</author>
<author>
<name sortKey="Lazarus, D D" uniqKey="Lazarus D">D.D. Lazarus</name>
</author>
<author>
<name sortKey="Maas, J" uniqKey="Maas J">J. Maas</name>
</author>
<author>
<name sortKey="Pien, C S" uniqKey="Pien C">C.S. Pien</name>
</author>
<author>
<name sortKey="Prakash, S" uniqKey="Prakash S">S. Prakash</name>
</author>
<author>
<name sortKey="Elliott, P J" uniqKey="Elliott P">P.J. Elliott</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Hideshima, T" uniqKey="Hideshima T">T. Hideshima</name>
</author>
<author>
<name sortKey="Mitsiades, C" uniqKey="Mitsiades C">C. Mitsiades</name>
</author>
<author>
<name sortKey="Akiyama, M" uniqKey="Akiyama M">M. Akiyama</name>
</author>
<author>
<name sortKey="Hayashi, T" uniqKey="Hayashi T">T. Hayashi</name>
</author>
<author>
<name sortKey="Chauhan, D" uniqKey="Chauhan D">D. Chauhan</name>
</author>
<author>
<name sortKey="Richardson, P" uniqKey="Richardson P">P. Richardson</name>
</author>
<author>
<name sortKey="Schlossman, R" uniqKey="Schlossman R">R. Schlossman</name>
</author>
<author>
<name sortKey="Podar, K" uniqKey="Podar K">K. Podar</name>
</author>
<author>
<name sortKey="Munshi, N C" uniqKey="Munshi N">N.C. Munshi</name>
</author>
<author>
<name sortKey="Mitsiades, N" uniqKey="Mitsiades N">N. Mitsiades</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Hideshima, T" uniqKey="Hideshima T">T. Hideshima</name>
</author>
<author>
<name sortKey="Richardson, P" uniqKey="Richardson P">P. Richardson</name>
</author>
<author>
<name sortKey="Chauhan, D" uniqKey="Chauhan D">D. Chauhan</name>
</author>
<author>
<name sortKey="Palombella, V J" uniqKey="Palombella V">V.J. Palombella</name>
</author>
<author>
<name sortKey="Elliott, P J" uniqKey="Elliott P">P.J. Elliott</name>
</author>
<author>
<name sortKey="Adams, J" uniqKey="Adams J">J. Adams</name>
</author>
<author>
<name sortKey="Anderson, K C" uniqKey="Anderson K">K.C. Anderson</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Leblanc, R" uniqKey="Leblanc R">R. LeBlanc</name>
</author>
<author>
<name sortKey="Catley, L P" uniqKey="Catley L">L.P. Catley</name>
</author>
<author>
<name sortKey="Hideshima, T" uniqKey="Hideshima T">T. Hideshima</name>
</author>
<author>
<name sortKey="Lentzsch, S" uniqKey="Lentzsch S">S. Lentzsch</name>
</author>
<author>
<name sortKey="Mitsiades, C S" uniqKey="Mitsiades C">C.S. Mitsiades</name>
</author>
<author>
<name sortKey="Mitsiades, N" uniqKey="Mitsiades N">N. Mitsiades</name>
</author>
<author>
<name sortKey="Neuberg, D" uniqKey="Neuberg D">D. Neuberg</name>
</author>
<author>
<name sortKey="Goloubeva, O" uniqKey="Goloubeva O">O. Goloubeva</name>
</author>
<author>
<name sortKey="Pien, C S" uniqKey="Pien C">C.S. Pien</name>
</author>
<author>
<name sortKey="Adams, J" uniqKey="Adams J">J. Adams</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Mitsiades, N" uniqKey="Mitsiades N">N. Mitsiades</name>
</author>
<author>
<name sortKey="Mitsiades, C S" uniqKey="Mitsiades C">C.S. Mitsiades</name>
</author>
<author>
<name sortKey="Poulaki, V" uniqKey="Poulaki V">V. Poulaki</name>
</author>
<author>
<name sortKey="Chauhan, D" uniqKey="Chauhan D">D. Chauhan</name>
</author>
<author>
<name sortKey="Fanourakis, G" uniqKey="Fanourakis G">G. Fanourakis</name>
</author>
<author>
<name sortKey="Gu, X" uniqKey="Gu X">X. Gu</name>
</author>
<author>
<name sortKey="Bailey, C" uniqKey="Bailey C">C. Bailey</name>
</author>
<author>
<name sortKey="Joseph, M" uniqKey="Joseph M">M. Joseph</name>
</author>
<author>
<name sortKey="Libermann, T A" uniqKey="Libermann T">T.A. Libermann</name>
</author>
<author>
<name sortKey="Treon, S P" uniqKey="Treon S">S.P. Treon</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Richardson, P G" uniqKey="Richardson P">P.G. Richardson</name>
</author>
<author>
<name sortKey="Barlogie, B" uniqKey="Barlogie B">B. Barlogie</name>
</author>
<author>
<name sortKey="Berenson, J" uniqKey="Berenson J">J. Berenson</name>
</author>
<author>
<name sortKey="Singhal, S" uniqKey="Singhal S">S. Singhal</name>
</author>
<author>
<name sortKey="Jagannath, S" uniqKey="Jagannath S">S. Jagannath</name>
</author>
<author>
<name sortKey="Irwin, D" uniqKey="Irwin D">D. Irwin</name>
</author>
<author>
<name sortKey="Rajkumar, S V" uniqKey="Rajkumar S">S.V. Rajkumar</name>
</author>
<author>
<name sortKey="Srkalovic, G" uniqKey="Srkalovic G">G. Srkalovic</name>
</author>
<author>
<name sortKey="Alsina, M" uniqKey="Alsina M">M. Alsina</name>
</author>
<author>
<name sortKey="Alexanian, R" uniqKey="Alexanian R">R. Alexanian</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Richardson, P G" uniqKey="Richardson P">P.G. Richardson</name>
</author>
<author>
<name sortKey="Sonneveld, P" uniqKey="Sonneveld P">P. Sonneveld</name>
</author>
<author>
<name sortKey="Schuster, M W" uniqKey="Schuster M">M.W. Schuster</name>
</author>
<author>
<name sortKey="Irwin, D" uniqKey="Irwin D">D. Irwin</name>
</author>
<author>
<name sortKey="Stadtmauer, E A" uniqKey="Stadtmauer E">E.A. Stadtmauer</name>
</author>
<author>
<name sortKey="Facon, T" uniqKey="Facon T">T. Facon</name>
</author>
<author>
<name sortKey="Harousseau, J L" uniqKey="Harousseau J">J.L. Harousseau</name>
</author>
<author>
<name sortKey="Ben Yehuda, D" uniqKey="Ben Yehuda D">D. Ben-Yehuda</name>
</author>
<author>
<name sortKey="Lonial, S" uniqKey="Lonial S">S. Lonial</name>
</author>
<author>
<name sortKey="Goldschmidt, H" uniqKey="Goldschmidt H">H. Goldschmidt</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Egan, J B" uniqKey="Egan J">J.B. Egan</name>
</author>
<author>
<name sortKey="Shi, C X" uniqKey="Shi C">C.X. Shi</name>
</author>
<author>
<name sortKey="Tembe, W" uniqKey="Tembe W">W. Tembe</name>
</author>
<author>
<name sortKey="Christoforides, A" uniqKey="Christoforides A">A. Christoforides</name>
</author>
<author>
<name sortKey="Kurdoglu, A" uniqKey="Kurdoglu A">A. Kurdoglu</name>
</author>
<author>
<name sortKey="Sinari, S" uniqKey="Sinari S">S. Sinari</name>
</author>
<author>
<name sortKey="Middha, S" uniqKey="Middha S">S. Middha</name>
</author>
<author>
<name sortKey="Asmann, Y" uniqKey="Asmann Y">Y. Asmann</name>
</author>
<author>
<name sortKey="Schmidt, J" uniqKey="Schmidt J">J. Schmidt</name>
</author>
<author>
<name sortKey="Braggio, E" uniqKey="Braggio E">E. Braggio</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Keats, J J" uniqKey="Keats J">J.J. Keats</name>
</author>
<author>
<name sortKey="Chesi, M" uniqKey="Chesi M">M. Chesi</name>
</author>
<author>
<name sortKey="Egan, J B" uniqKey="Egan J">J.B. Egan</name>
</author>
<author>
<name sortKey="Garbitt, V M" uniqKey="Garbitt V">V.M. Garbitt</name>
</author>
<author>
<name sortKey="Palmer, S E" uniqKey="Palmer S">S.E. Palmer</name>
</author>
<author>
<name sortKey="Braggio, E" uniqKey="Braggio E">E. Braggio</name>
</author>
<author>
<name sortKey="Van Wier, S" uniqKey="Van Wier S">S. Van Wier</name>
</author>
<author>
<name sortKey="Blackburn, P R" uniqKey="Blackburn P">P.R. Blackburn</name>
</author>
<author>
<name sortKey="Baker, A S" uniqKey="Baker A">A.S. Baker</name>
</author>
<author>
<name sortKey="Dispenzieri, A" uniqKey="Dispenzieri A">A. Dispenzieri</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Magrangeas, F" uniqKey="Magrangeas F">F. Magrangeas</name>
</author>
<author>
<name sortKey="Avet Loiseau, H" uniqKey="Avet Loiseau H">H. Avet-Loiseau</name>
</author>
<author>
<name sortKey="Gouraud, W" uniqKey="Gouraud W">W. Gouraud</name>
</author>
<author>
<name sortKey="Lode, L" uniqKey="Lode L">L. Lode</name>
</author>
<author>
<name sortKey="Decaux, O" uniqKey="Decaux O">O. Decaux</name>
</author>
<author>
<name sortKey="Godmer, P" uniqKey="Godmer P">P. Godmer</name>
</author>
<author>
<name sortKey="Garderet, L" uniqKey="Garderet L">L. Garderet</name>
</author>
<author>
<name sortKey="Voillat, L" uniqKey="Voillat L">L. Voillat</name>
</author>
<author>
<name sortKey="Facon, T" uniqKey="Facon T">T. Facon</name>
</author>
<author>
<name sortKey="Stoppa, A M" uniqKey="Stoppa A">A.M. Stoppa</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Boudreault, J S" uniqKey="Boudreault J">J.S. Boudreault</name>
</author>
<author>
<name sortKey="Touzeau, C" uniqKey="Touzeau C">C. Touzeau</name>
</author>
<author>
<name sortKey="Moreau, P" uniqKey="Moreau P">P. Moreau</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Chhabra, S" uniqKey="Chhabra S">S. Chhabra</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Desantis, V" uniqKey="Desantis V">V. Desantis</name>
</author>
<author>
<name sortKey="Saltarella, I" uniqKey="Saltarella I">I. Saltarella</name>
</author>
<author>
<name sortKey="Lamanuzzi, A" uniqKey="Lamanuzzi A">A. Lamanuzzi</name>
</author>
<author>
<name sortKey="Mariggio, M A" uniqKey="Mariggio M">M.A. Mariggio</name>
</author>
<author>
<name sortKey="Racanelli, V" uniqKey="Racanelli V">V. Racanelli</name>
</author>
<author>
<name sortKey="Vacca, A" uniqKey="Vacca A">A. Vacca</name>
</author>
<author>
<name sortKey="Frassanito, M A" uniqKey="Frassanito M">M.A. Frassanito</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Ding, W X" uniqKey="Ding W">W.X. Ding</name>
</author>
<author>
<name sortKey="Ni, H M" uniqKey="Ni H">H.M. Ni</name>
</author>
<author>
<name sortKey="Gao, W" uniqKey="Gao W">W. Gao</name>
</author>
<author>
<name sortKey="Yoshimori, T" uniqKey="Yoshimori T">T. Yoshimori</name>
</author>
<author>
<name sortKey="Stolz, D B" uniqKey="Stolz D">D.B. Stolz</name>
</author>
<author>
<name sortKey="Ron, D" uniqKey="Ron D">D. Ron</name>
</author>
<author>
<name sortKey="Yin, X M" uniqKey="Yin X">X.M. Yin</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Li, S" uniqKey="Li S">S. Li</name>
</author>
<author>
<name sortKey="Wang, L" uniqKey="Wang L">L. Wang</name>
</author>
<author>
<name sortKey="Hu, Y" uniqKey="Hu Y">Y. Hu</name>
</author>
<author>
<name sortKey="Sheng, R" uniqKey="Sheng R">R. Sheng</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Frassanito, M A" uniqKey="Frassanito M">M.A. Frassanito</name>
</author>
<author>
<name sortKey="De Veirman, K" uniqKey="De Veirman K">K. De Veirman</name>
</author>
<author>
<name sortKey="Desantis, V" uniqKey="Desantis V">V. Desantis</name>
</author>
<author>
<name sortKey="Di Marzo, L" uniqKey="Di Marzo L">L. Di Marzo</name>
</author>
<author>
<name sortKey="Vergara, D" uniqKey="Vergara D">D. Vergara</name>
</author>
<author>
<name sortKey="Ruggieri, S" uniqKey="Ruggieri S">S. Ruggieri</name>
</author>
<author>
<name sortKey="Annese, T" uniqKey="Annese T">T. Annese</name>
</author>
<author>
<name sortKey="Nico, B" uniqKey="Nico B">B. Nico</name>
</author>
<author>
<name sortKey="Menu, E" uniqKey="Menu E">E. Menu</name>
</author>
<author>
<name sortKey="Catacchio, I" uniqKey="Catacchio I">I. Catacchio</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Hideshima, T" uniqKey="Hideshima T">T. Hideshima</name>
</author>
<author>
<name sortKey="Bradner, J E" uniqKey="Bradner J">J.E. Bradner</name>
</author>
<author>
<name sortKey="Wong, J" uniqKey="Wong J">J. Wong</name>
</author>
<author>
<name sortKey="Chauhan, D" uniqKey="Chauhan D">D. Chauhan</name>
</author>
<author>
<name sortKey="Richardson, P" uniqKey="Richardson P">P. Richardson</name>
</author>
<author>
<name sortKey="Schreiber, S L" uniqKey="Schreiber S">S.L. Schreiber</name>
</author>
<author>
<name sortKey="Anderson, K C" uniqKey="Anderson K">K.C. Anderson</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Amaravadi, R K" uniqKey="Amaravadi R">R.K. Amaravadi</name>
</author>
<author>
<name sortKey="Lippincott Schwartz, J" uniqKey="Lippincott Schwartz J">J. Lippincott-Schwartz</name>
</author>
<author>
<name sortKey="Yin, X M" uniqKey="Yin X">X.M. Yin</name>
</author>
<author>
<name sortKey="Weiss, W A" uniqKey="Weiss W">W.A. Weiss</name>
</author>
<author>
<name sortKey="Takebe, N" uniqKey="Takebe N">N. Takebe</name>
</author>
<author>
<name sortKey="Timmer, W" uniqKey="Timmer W">W. Timmer</name>
</author>
<author>
<name sortKey="Dipaola, R S" uniqKey="Dipaola R">R.S. DiPaola</name>
</author>
<author>
<name sortKey="Lotze, M T" uniqKey="Lotze M">M.T. Lotze</name>
</author>
<author>
<name sortKey="White, E" uniqKey="White E">E. White</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Hui, B" uniqKey="Hui B">B. Hui</name>
</author>
<author>
<name sortKey="Shi, Y H" uniqKey="Shi Y">Y.H. Shi</name>
</author>
<author>
<name sortKey="Ding, Z B" uniqKey="Ding Z">Z.B. Ding</name>
</author>
<author>
<name sortKey="Zhou, J" uniqKey="Zhou J">J. Zhou</name>
</author>
<author>
<name sortKey="Gu, C Y" uniqKey="Gu C">C.Y. Gu</name>
</author>
<author>
<name sortKey="Peng, Y F" uniqKey="Peng Y">Y.F. Peng</name>
</author>
<author>
<name sortKey="Yang, H" uniqKey="Yang H">H. Yang</name>
</author>
<author>
<name sortKey="Liu, W R" uniqKey="Liu W">W.R. Liu</name>
</author>
<author>
<name sortKey="Shi, G M" uniqKey="Shi G">G.M. Shi</name>
</author>
<author>
<name sortKey="Fan, J" uniqKey="Fan J">J. Fan</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Jia, L" uniqKey="Jia L">L. Jia</name>
</author>
<author>
<name sortKey="Gopinathan, G" uniqKey="Gopinathan G">G. Gopinathan</name>
</author>
<author>
<name sortKey="Sukumar, J T" uniqKey="Sukumar J">J.T. Sukumar</name>
</author>
<author>
<name sortKey="Gribben, J G" uniqKey="Gribben J">J.G. Gribben</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Milani, M" uniqKey="Milani M">M. Milani</name>
</author>
<author>
<name sortKey="Rzymski, T" uniqKey="Rzymski T">T. Rzymski</name>
</author>
<author>
<name sortKey="Mellor, H R" uniqKey="Mellor H">H.R. Mellor</name>
</author>
<author>
<name sortKey="Pike, L" uniqKey="Pike L">L. Pike</name>
</author>
<author>
<name sortKey="Bottini, A" uniqKey="Bottini A">A. Bottini</name>
</author>
<author>
<name sortKey="Generali, D" uniqKey="Generali D">D. Generali</name>
</author>
<author>
<name sortKey="Harris, A L" uniqKey="Harris A">A.L. Harris</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Yao, F" uniqKey="Yao F">F. Yao</name>
</author>
<author>
<name sortKey="Wang, G" uniqKey="Wang G">G. Wang</name>
</author>
<author>
<name sortKey="Wei, W" uniqKey="Wei W">W. Wei</name>
</author>
<author>
<name sortKey="Tu, Y" uniqKey="Tu Y">Y. Tu</name>
</author>
<author>
<name sortKey="Tong, H" uniqKey="Tong H">H. Tong</name>
</author>
<author>
<name sortKey="Sun, S" uniqKey="Sun S">S. Sun</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Escalante, A M" uniqKey="Escalante A">A.M. Escalante</name>
</author>
<author>
<name sortKey="Mcgrath, R T" uniqKey="Mcgrath R">R.T. McGrath</name>
</author>
<author>
<name sortKey="Karolak, M R" uniqKey="Karolak M">M.R. Karolak</name>
</author>
<author>
<name sortKey="Dorr, R T" uniqKey="Dorr R">R.T. Dorr</name>
</author>
<author>
<name sortKey="Lynch, R M" uniqKey="Lynch R">R.M. Lynch</name>
</author>
<author>
<name sortKey="Landowski, T H" uniqKey="Landowski T">T.H. Landowski</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Kawaguchi, T" uniqKey="Kawaguchi T">T. Kawaguchi</name>
</author>
<author>
<name sortKey="Miyazawa, K" uniqKey="Miyazawa K">K. Miyazawa</name>
</author>
<author>
<name sortKey="Moriya, S" uniqKey="Moriya S">S. Moriya</name>
</author>
<author>
<name sortKey="Ohtomo, T" uniqKey="Ohtomo T">T. Ohtomo</name>
</author>
<author>
<name sortKey="Che, X F" uniqKey="Che X">X.F. Che</name>
</author>
<author>
<name sortKey="Naito, M" uniqKey="Naito M">M. Naito</name>
</author>
<author>
<name sortKey="Itoh, M" uniqKey="Itoh M">M. Itoh</name>
</author>
<author>
<name sortKey="Tomoda, A" uniqKey="Tomoda A">A. Tomoda</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Ding, W X" uniqKey="Ding W">W.X. Ding</name>
</author>
<author>
<name sortKey="Ni, H M" uniqKey="Ni H">H.M. Ni</name>
</author>
<author>
<name sortKey="Gao, W" uniqKey="Gao W">W. Gao</name>
</author>
<author>
<name sortKey="Chen, X" uniqKey="Chen X">X. Chen</name>
</author>
<author>
<name sortKey="Kang, J H" uniqKey="Kang J">J.H. Kang</name>
</author>
<author>
<name sortKey="Stolz, D B" uniqKey="Stolz D">D.B. Stolz</name>
</author>
<author>
<name sortKey="Liu, J" uniqKey="Liu J">J. Liu</name>
</author>
<author>
<name sortKey="Yin, X M" uniqKey="Yin X">X.M. Yin</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Amaravadi, R K" uniqKey="Amaravadi R">R.K. Amaravadi</name>
</author>
<author>
<name sortKey="Yu, D" uniqKey="Yu D">D. Yu</name>
</author>
<author>
<name sortKey="Lum, J J" uniqKey="Lum J">J.J. Lum</name>
</author>
<author>
<name sortKey="Bui, T" uniqKey="Bui T">T. Bui</name>
</author>
<author>
<name sortKey="Christophorou, M A" uniqKey="Christophorou M">M.A. Christophorou</name>
</author>
<author>
<name sortKey="Evan, G I" uniqKey="Evan G">G.I. Evan</name>
</author>
<author>
<name sortKey="Thomas Tikhonenko, A" uniqKey="Thomas Tikhonenko A">A. Thomas-Tikhonenko</name>
</author>
<author>
<name sortKey="Thompson, C B" uniqKey="Thompson C">C.B. Thompson</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Frieboes, H B" uniqKey="Frieboes H">H.B. Frieboes</name>
</author>
<author>
<name sortKey="Huang, J S" uniqKey="Huang J">J.S. Huang</name>
</author>
<author>
<name sortKey="Yin, W C" uniqKey="Yin W">W.C. Yin</name>
</author>
<author>
<name sortKey="Mcnally, L R" uniqKey="Mcnally L">L.R. McNally</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Long, L" uniqKey="Long L">L. Long</name>
</author>
<author>
<name sortKey="Yang, X" uniqKey="Yang X">X. Yang</name>
</author>
<author>
<name sortKey="Southwood, M" uniqKey="Southwood M">M. Southwood</name>
</author>
<author>
<name sortKey="Lu, J" uniqKey="Lu J">J. Lu</name>
</author>
<author>
<name sortKey="Marciniak, S J" uniqKey="Marciniak S">S.J. Marciniak</name>
</author>
<author>
<name sortKey="Dunmore, B J" uniqKey="Dunmore B">B.J. Dunmore</name>
</author>
<author>
<name sortKey="Morrell, N W" uniqKey="Morrell N">N.W. Morrell</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Akdemir, G" uniqKey="Akdemir G">G. Akdemir</name>
</author>
<author>
<name sortKey="Heimans, L" uniqKey="Heimans L">L. Heimans</name>
</author>
<author>
<name sortKey="Bergstra, S A" uniqKey="Bergstra S">S.A. Bergstra</name>
</author>
<author>
<name sortKey="Goekoop, R J" uniqKey="Goekoop R">R.J. Goekoop</name>
</author>
<author>
<name sortKey="Van Oosterhout, M" uniqKey="Van Oosterhout M">M. van Oosterhout</name>
</author>
<author>
<name sortKey="Van Groenendael, J" uniqKey="Van Groenendael J">J. van Groenendael</name>
</author>
<author>
<name sortKey="Peeters, A J" uniqKey="Peeters A">A.J. Peeters</name>
</author>
<author>
<name sortKey="Steup Beekman, G M" uniqKey="Steup Beekman G">G.M. Steup-Beekman</name>
</author>
<author>
<name sortKey="Lard, L R" uniqKey="Lard L">L.R. Lard</name>
</author>
<author>
<name sortKey="De Sonnaville, P B J" uniqKey="De Sonnaville P">P.B.J. de Sonnaville</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Hsu, C Y" uniqKey="Hsu C">C.Y. Hsu</name>
</author>
<author>
<name sortKey="Lin, Y S" uniqKey="Lin Y">Y.S. Lin</name>
</author>
<author>
<name sortKey="Su, Y J" uniqKey="Su Y">Y.J. Su</name>
</author>
<author>
<name sortKey="Lin, H F" uniqKey="Lin H">H.F. Lin</name>
</author>
<author>
<name sortKey="Lin, M S" uniqKey="Lin M">M.S. Lin</name>
</author>
<author>
<name sortKey="Syu, Y J" uniqKey="Syu Y">Y.J. Syu</name>
</author>
<author>
<name sortKey="Cheng, T T" uniqKey="Cheng T">T.T. Cheng</name>
</author>
<author>
<name sortKey="Yu, S F" uniqKey="Yu S">S.F. Yu</name>
</author>
<author>
<name sortKey="Chen, J F" uniqKey="Chen J">J.F. Chen</name>
</author>
<author>
<name sortKey="Chen, T H" uniqKey="Chen T">T.H. Chen</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Rempenault, C" uniqKey="Rempenault C">C. Rempenault</name>
</author>
<author>
<name sortKey="Combe, B" uniqKey="Combe B">B. Combe</name>
</author>
<author>
<name sortKey="Barnetche, T" uniqKey="Barnetche T">T. Barnetche</name>
</author>
<author>
<name sortKey="Gaujoux Viala, C" uniqKey="Gaujoux Viala C">C. Gaujoux-Viala</name>
</author>
<author>
<name sortKey="Lukas, C" uniqKey="Lukas C">C. Lukas</name>
</author>
<author>
<name sortKey="Morel, J" uniqKey="Morel J">J. Morel</name>
</author>
<author>
<name sortKey="Hua, C" uniqKey="Hua C">C. Hua</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Vogl, D T" uniqKey="Vogl D">D.T. Vogl</name>
</author>
<author>
<name sortKey="Stadtmauer, E A" uniqKey="Stadtmauer E">E.A. Stadtmauer</name>
</author>
<author>
<name sortKey="Tan, K S" uniqKey="Tan K">K.S. Tan</name>
</author>
<author>
<name sortKey="Heitjan, D F" uniqKey="Heitjan D">D.F. Heitjan</name>
</author>
<author>
<name sortKey="Davis, L E" uniqKey="Davis L">L.E. Davis</name>
</author>
<author>
<name sortKey="Pontiggia, L" uniqKey="Pontiggia L">L. Pontiggia</name>
</author>
<author>
<name sortKey="Rangwala, R" uniqKey="Rangwala R">R. Rangwala</name>
</author>
<author>
<name sortKey="Piao, S" uniqKey="Piao S">S. Piao</name>
</author>
<author>
<name sortKey="Chang, Y C" uniqKey="Chang Y">Y.C. Chang</name>
</author>
<author>
<name sortKey="Scott, E C" uniqKey="Scott E">E.C. Scott</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Mizushima, N" uniqKey="Mizushima N">N. Mizushima</name>
</author>
<author>
<name sortKey="Yoshimori, T" uniqKey="Yoshimori T">T. Yoshimori</name>
</author>
<author>
<name sortKey="Levine, B" uniqKey="Levine B">B. Levine</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Bjorkoy, G" uniqKey="Bjorkoy G">G. Bjorkoy</name>
</author>
<author>
<name sortKey="Lamark, T" uniqKey="Lamark T">T. Lamark</name>
</author>
<author>
<name sortKey="Pankiv, S" uniqKey="Pankiv S">S. Pankiv</name>
</author>
<author>
<name sortKey="Overvatn, A" uniqKey="Overvatn A">A. Overvatn</name>
</author>
<author>
<name sortKey="Brech, A" uniqKey="Brech A">A. Brech</name>
</author>
<author>
<name sortKey="Johansen, T" uniqKey="Johansen T">T. Johansen</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Roccaro, A M" uniqKey="Roccaro A">A.M. Roccaro</name>
</author>
<author>
<name sortKey="Hideshima, T" uniqKey="Hideshima T">T. Hideshima</name>
</author>
<author>
<name sortKey="Raje, N" uniqKey="Raje N">N. Raje</name>
</author>
<author>
<name sortKey="Kumar, S" uniqKey="Kumar S">S. Kumar</name>
</author>
<author>
<name sortKey="Ishitsuka, K" uniqKey="Ishitsuka K">K. Ishitsuka</name>
</author>
<author>
<name sortKey="Yasui, H" uniqKey="Yasui H">H. Yasui</name>
</author>
<author>
<name sortKey="Shiraishi, N" uniqKey="Shiraishi N">N. Shiraishi</name>
</author>
<author>
<name sortKey="Ribatti, D" uniqKey="Ribatti D">D. Ribatti</name>
</author>
<author>
<name sortKey="Nico, B" uniqKey="Nico B">B. Nico</name>
</author>
<author>
<name sortKey="Vacca, A" uniqKey="Vacca A">A. Vacca</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Avet Loiseau, H" uniqKey="Avet Loiseau H">H. Avet-Loiseau</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Jarauta, V" uniqKey="Jarauta V">V. Jarauta</name>
</author>
<author>
<name sortKey="Jaime, P" uniqKey="Jaime P">P. Jaime</name>
</author>
<author>
<name sortKey="Gonzalo, O" uniqKey="Gonzalo O">O. Gonzalo</name>
</author>
<author>
<name sortKey="De Miguel, D" uniqKey="De Miguel D">D. de Miguel</name>
</author>
<author>
<name sortKey="Ramirez Labrada, A" uniqKey="Ramirez Labrada A">A. Ramirez-Labrada</name>
</author>
<author>
<name sortKey="Martinez Lostao, L" uniqKey="Martinez Lostao L">L. Martinez-Lostao</name>
</author>
<author>
<name sortKey="Anel, A" uniqKey="Anel A">A. Anel</name>
</author>
<author>
<name sortKey="Pardo, J" uniqKey="Pardo J">J. Pardo</name>
</author>
<author>
<name sortKey="Marzo, I" uniqKey="Marzo I">I. Marzo</name>
</author>
<author>
<name sortKey="Naval, J" uniqKey="Naval J">J. Naval</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Bianchi, G" uniqKey="Bianchi G">G. Bianchi</name>
</author>
<author>
<name sortKey="Oliva, L" uniqKey="Oliva L">L. Oliva</name>
</author>
<author>
<name sortKey="Cascio, P" uniqKey="Cascio P">P. Cascio</name>
</author>
<author>
<name sortKey="Pengo, N" uniqKey="Pengo N">N. Pengo</name>
</author>
<author>
<name sortKey="Fontana, F" uniqKey="Fontana F">F. Fontana</name>
</author>
<author>
<name sortKey="Cerruti, F" uniqKey="Cerruti F">F. Cerruti</name>
</author>
<author>
<name sortKey="Orsi, A" uniqKey="Orsi A">A. Orsi</name>
</author>
<author>
<name sortKey="Pasqualetto, E" uniqKey="Pasqualetto E">E. Pasqualetto</name>
</author>
<author>
<name sortKey="Mezghrani, A" uniqKey="Mezghrani A">A. Mezghrani</name>
</author>
<author>
<name sortKey="Calbi, V" uniqKey="Calbi V">V. Calbi</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Racanelli, V" uniqKey="Racanelli V">V. Racanelli</name>
</author>
<author>
<name sortKey="Leone, P" uniqKey="Leone P">P. Leone</name>
</author>
<author>
<name sortKey="Frassanito, M A" uniqKey="Frassanito M">M.A. Frassanito</name>
</author>
<author>
<name sortKey="Brunetti, C" uniqKey="Brunetti C">C. Brunetti</name>
</author>
<author>
<name sortKey="Perosa, F" uniqKey="Perosa F">F. Perosa</name>
</author>
<author>
<name sortKey="Ferrone, S" uniqKey="Ferrone S">S. Ferrone</name>
</author>
<author>
<name sortKey="Dammacco, F" uniqKey="Dammacco F">F. Dammacco</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Kouroku, Y" uniqKey="Kouroku Y">Y. Kouroku</name>
</author>
<author>
<name sortKey="Fujita, E" uniqKey="Fujita E">E. Fujita</name>
</author>
<author>
<name sortKey="Tanida, I" uniqKey="Tanida I">I. Tanida</name>
</author>
<author>
<name sortKey="Ueno, T" uniqKey="Ueno T">T. Ueno</name>
</author>
<author>
<name sortKey="Isoai, A" uniqKey="Isoai A">A. Isoai</name>
</author>
<author>
<name sortKey="Kumagai, H" uniqKey="Kumagai H">H. Kumagai</name>
</author>
<author>
<name sortKey="Ogawa, S" uniqKey="Ogawa S">S. Ogawa</name>
</author>
<author>
<name sortKey="Kaufman, R J" uniqKey="Kaufman R">R.J. Kaufman</name>
</author>
<author>
<name sortKey="Kominami, E" uniqKey="Kominami E">E. Kominami</name>
</author>
<author>
<name sortKey="Momoi, T" uniqKey="Momoi T">T. Momoi</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Ogata, M" uniqKey="Ogata M">M. Ogata</name>
</author>
<author>
<name sortKey="Hino, S" uniqKey="Hino S">S. Hino</name>
</author>
<author>
<name sortKey="Saito, A" uniqKey="Saito A">A. Saito</name>
</author>
<author>
<name sortKey="Morikawa, K" uniqKey="Morikawa K">K. Morikawa</name>
</author>
<author>
<name sortKey="Kondo, S" uniqKey="Kondo S">S. Kondo</name>
</author>
<author>
<name sortKey="Kanemoto, S" uniqKey="Kanemoto S">S. Kanemoto</name>
</author>
<author>
<name sortKey="Murakami, T" uniqKey="Murakami T">T. Murakami</name>
</author>
<author>
<name sortKey="Taniguchi, M" uniqKey="Taniguchi M">M. Taniguchi</name>
</author>
<author>
<name sortKey="Tanii, I" uniqKey="Tanii I">I. Tanii</name>
</author>
<author>
<name sortKey="Yoshinaga, K" uniqKey="Yoshinaga K">K. Yoshinaga</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Kawano, Y" uniqKey="Kawano Y">Y. Kawano</name>
</author>
<author>
<name sortKey="Moschetta, M" uniqKey="Moschetta M">M. Moschetta</name>
</author>
<author>
<name sortKey="Manier, S" uniqKey="Manier S">S. Manier</name>
</author>
<author>
<name sortKey="Glavey, S" uniqKey="Glavey S">S. Glavey</name>
</author>
<author>
<name sortKey="Gorgun, G T" uniqKey="Gorgun G">G.T. Gorgun</name>
</author>
<author>
<name sortKey="Roccaro, A M" uniqKey="Roccaro A">A.M. Roccaro</name>
</author>
<author>
<name sortKey="Anderson, K C" uniqKey="Anderson K">K.C. Anderson</name>
</author>
<author>
<name sortKey="Ghobrial, I M" uniqKey="Ghobrial I">I.M. Ghobrial</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Ribatti, D" uniqKey="Ribatti D">D. Ribatti</name>
</author>
<author>
<name sortKey="Vacca, A" uniqKey="Vacca A">A. Vacca</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Holczer, M" uniqKey="Holczer M">M. Holczer</name>
</author>
<author>
<name sortKey="Marton, M" uniqKey="Marton M">M. Marton</name>
</author>
<author>
<name sortKey="Kurucz, A" uniqKey="Kurucz A">A. Kurucz</name>
</author>
<author>
<name sortKey="Banhegyi, G" uniqKey="Banhegyi G">G. Banhegyi</name>
</author>
<author>
<name sortKey="Kapuy, O" uniqKey="Kapuy O">O. Kapuy</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Rao, S" uniqKey="Rao S">S. Rao</name>
</author>
<author>
<name sortKey="Tortola, L" uniqKey="Tortola L">L. Tortola</name>
</author>
<author>
<name sortKey="Perlot, T" uniqKey="Perlot T">T. Perlot</name>
</author>
<author>
<name sortKey="Wirnsberger, G" uniqKey="Wirnsberger G">G. Wirnsberger</name>
</author>
<author>
<name sortKey="Novatchkova, M" uniqKey="Novatchkova M">M. Novatchkova</name>
</author>
<author>
<name sortKey="Nitsch, R" uniqKey="Nitsch R">R. Nitsch</name>
</author>
<author>
<name sortKey="Sykacek, P" uniqKey="Sykacek P">P. Sykacek</name>
</author>
<author>
<name sortKey="Frank, L" uniqKey="Frank L">L. Frank</name>
</author>
<author>
<name sortKey="Schramek, D" uniqKey="Schramek D">D. Schramek</name>
</author>
<author>
<name sortKey="Komnenovic, V" uniqKey="Komnenovic V">V. Komnenovic</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Leone, P" uniqKey="Leone P">P. Leone</name>
</author>
<author>
<name sortKey="Di Lernia, G" uniqKey="Di Lernia G">G. Di Lernia</name>
</author>
<author>
<name sortKey="Solimando, A G" uniqKey="Solimando A">A.G. Solimando</name>
</author>
<author>
<name sortKey="Cicco, S" uniqKey="Cicco S">S. Cicco</name>
</author>
<author>
<name sortKey="Saltarella, I" uniqKey="Saltarella I">I. Saltarella</name>
</author>
<author>
<name sortKey="Lamanuzzi, A" uniqKey="Lamanuzzi A">A. Lamanuzzi</name>
</author>
<author>
<name sortKey="Ria, R" uniqKey="Ria R">R. Ria</name>
</author>
<author>
<name sortKey="Frassanito, M A" uniqKey="Frassanito M">M.A. Frassanito</name>
</author>
<author>
<name sortKey="Ponzoni, M" uniqKey="Ponzoni M">M. Ponzoni</name>
</author>
<author>
<name sortKey="Ditonno, P" uniqKey="Ditonno P">P. Ditonno</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Frassanito, M A" uniqKey="Frassanito M">M.A. Frassanito</name>
</author>
<author>
<name sortKey="Desantis, V" uniqKey="Desantis V">V. Desantis</name>
</author>
<author>
<name sortKey="Di Marzo, L" uniqKey="Di Marzo L">L. Di Marzo</name>
</author>
<author>
<name sortKey="Craparotta, I" uniqKey="Craparotta I">I. Craparotta</name>
</author>
<author>
<name sortKey="Beltrame, L" uniqKey="Beltrame L">L. Beltrame</name>
</author>
<author>
<name sortKey="Marchini, S" uniqKey="Marchini S">S. Marchini</name>
</author>
<author>
<name sortKey="Annese, T" uniqKey="Annese T">T. Annese</name>
</author>
<author>
<name sortKey="Visino, F" uniqKey="Visino F">F. Visino</name>
</author>
<author>
<name sortKey="Arciuli, M" uniqKey="Arciuli M">M. Arciuli</name>
</author>
<author>
<name sortKey="Saltarella, I" uniqKey="Saltarella I">I. Saltarella</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Solimando, A G" uniqKey="Solimando A">A.G. Solimando</name>
</author>
<author>
<name sortKey="Da Via, M C" uniqKey="Da Via M">M.C. Da Via</name>
</author>
<author>
<name sortKey="Cicco, S" uniqKey="Cicco S">S. Cicco</name>
</author>
<author>
<name sortKey="Leone, P" uniqKey="Leone P">P. Leone</name>
</author>
<author>
<name sortKey="Di Lernia, G" uniqKey="Di Lernia G">G. Di Lernia</name>
</author>
<author>
<name sortKey="Giannico, D" uniqKey="Giannico D">D. Giannico</name>
</author>
<author>
<name sortKey="Desantis, V" uniqKey="Desantis V">V. Desantis</name>
</author>
<author>
<name sortKey="Frassanito, M A" uniqKey="Frassanito M">M.A. Frassanito</name>
</author>
<author>
<name sortKey="Morizio, A" uniqKey="Morizio A">A. Morizio</name>
</author>
<author>
<name sortKey="Delgado Tascon, J" uniqKey="Delgado Tascon J">J. Delgado Tascon</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Snel, B" uniqKey="Snel B">B. Snel</name>
</author>
<author>
<name sortKey="Lehmann, G" uniqKey="Lehmann G">G. Lehmann</name>
</author>
<author>
<name sortKey="Bork, P" uniqKey="Bork P">P. Bork</name>
</author>
<author>
<name sortKey="Huynen, M A" uniqKey="Huynen M">M.A. Huynen</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Szklarczyk, D" uniqKey="Szklarczyk D">D. Szklarczyk</name>
</author>
<author>
<name sortKey="Gable, A L" uniqKey="Gable A">A.L. Gable</name>
</author>
<author>
<name sortKey="Lyon, D" uniqKey="Lyon D">D. Lyon</name>
</author>
<author>
<name sortKey="Junge, A" uniqKey="Junge A">A. Junge</name>
</author>
<author>
<name sortKey="Wyder, S" uniqKey="Wyder S">S. Wyder</name>
</author>
<author>
<name sortKey="Huerta Cepas, J" uniqKey="Huerta Cepas J">J. Huerta-Cepas</name>
</author>
<author>
<name sortKey="Simonovic, M" uniqKey="Simonovic M">M. Simonovic</name>
</author>
<author>
<name sortKey="Doncheva, N T" uniqKey="Doncheva N">N.T. Doncheva</name>
</author>
<author>
<name sortKey="Morris, J H" uniqKey="Morris J">J.H. Morris</name>
</author>
<author>
<name sortKey="Bork, P" uniqKey="Bork P">P. Bork</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<pmc article-type="research-article">
<pmc-dir>properties open_access</pmc-dir>
<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">J Clin Med</journal-id>
<journal-id journal-id-type="iso-abbrev">J Clin Med</journal-id>
<journal-id journal-id-type="publisher-id">jcm</journal-id>
<journal-title-group>
<journal-title>Journal of Clinical Medicine</journal-title>
</journal-title-group>
<issn pub-type="epub">2077-0383</issn>
<publisher>
<publisher-name>MDPI</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">32085480</article-id>
<article-id pub-id-type="pmc">7073518</article-id>
<article-id pub-id-type="doi">10.3390/jcm9020552</article-id>
<article-id pub-id-type="publisher-id">jcm-09-00552</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Article</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Bortezomib Treatment Modulates Autophagy in Multiple Myeloma</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-8181-5986</contrib-id>
<name>
<surname>Di Lernia</surname>
<given-names>Giuseppe</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
<xref ref-type="author-notes" rid="fn1-jcm-09-00552">†</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-0904-1074</contrib-id>
<name>
<surname>Leone</surname>
<given-names>Patrizia</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
<xref ref-type="author-notes" rid="fn1-jcm-09-00552">†</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-2293-9698</contrib-id>
<name>
<surname>Solimando</surname>
<given-names>Antonio Giovanni</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
<xref ref-type="aff" rid="af2-jcm-09-00552">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Buonavoglia</surname>
<given-names>Alessio</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Saltarella</surname>
<given-names>Ilaria</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-1515-0090</contrib-id>
<name>
<surname>Ria</surname>
<given-names>Roberto</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Ditonno</surname>
<given-names>Paolo</given-names>
</name>
<xref ref-type="aff" rid="af2-jcm-09-00552">2</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-7814-7318</contrib-id>
<name>
<surname>Silvestris</surname>
<given-names>Nicola</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
<xref ref-type="aff" rid="af2-jcm-09-00552">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Crudele</surname>
<given-names>Lucilla</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-4567-8216</contrib-id>
<name>
<surname>Vacca</surname>
<given-names>Angelo</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-8639-1940</contrib-id>
<name>
<surname>Racanelli</surname>
<given-names>Vito</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
<xref rid="c1-jcm-09-00552" ref-type="corresp">*</xref>
</contrib>
</contrib-group>
<aff id="af1-jcm-09-00552">
<label>1</label>
Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;
<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);
<email>patrizia.leone@uniba.it</email>
(P.L.);
<email>antoniogiovannisolimando@gmail.com</email>
(A.G.S.);
<email>alessio.buonavoglia85@gmail.com</email>
(A.B.);
<email>ilaria.saltarella@libero.it</email>
(I.S.);
<email>roberto.ria@uniba.it</email>
(R.R.);
<email>n.silvestris@oncologico.bari.it</email>
(N.S.);
<email>lucillacrudele@gmail.com</email>
(L.C.);
<email>angelo.vacca@uniba.it</email>
(A.V.)</aff>
<aff id="af2-jcm-09-00552">
<label>2</label>
IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;
<email>paolo.ditonno@fastwebnet.it</email>
</aff>
<author-notes>
<corresp id="c1-jcm-09-00552">
<label>*</label>
Correspondence:
<email>vito.racanelli1@uniba.it</email>
</corresp>
<fn id="fn1-jcm-09-00552">
<label>†</label>
<p>Giuseppe Di Lernia and Patrizia Leone contributed equally to this work and should be considered co-first authors.</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>18</day>
<month>2</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="collection">
<month>2</month>
<year>2020</year>
</pub-date>
<volume>9</volume>
<issue>2</issue>
<elocation-id>552</elocation-id>
<history>
<date date-type="received">
<day>16</day>
<month>1</month>
<year>2020</year>
</date>
<date date-type="accepted">
<day>13</day>
<month>2</month>
<year>2020</year>
</date>
</history>
<permissions>
<copyright-statement>© 2020 by the authors.</copyright-statement>
<copyright-year>2020</copyright-year>
<license license-type="open-access">
<license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (
<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
).</license-p>
</license>
</permissions>
<abstract>
<p>Although the introduction of bortezomib as a therapeutic strategy has improved the overall survival of multiple myeloma (MM) patients, 15–20% of high-risk patients do not respond to bortezomib over time or become resistant to treatment. Therefore, the development of new therapeutic strategies, such as combination therapies, is urgently needed. Methods: Given that bortezomib resistance may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation, and that an enormous amounts of misfolded protein is generated in myeloma plasma cells (PCs), we investigated the effect of the simultaneous inhibition of proteasome by bortezomib and autophagy by hydroxychloroquine (HCQ) treatment on PCs and endothelial cells (ECs) isolated from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM. Results: We found that bortezomib combined with HCQ induces synergistic cytotoxicity in myeloma PCs whereas this effect is lost on ECs. Levels of microtubule-associated protein light chain beta (LC3B) and p62 are differentially modulated in PCs and ECs, with effects on cell viability and proliferation. Conclusions: Our results suggest that treatment with bortezomib and HCQ should be associated with an anti-angiogenic drug to prevent the pro-angiogenic effect of bortezomib, the proliferation of a small residual tumor PC clone, and thus the relapse.</p>
</abstract>
<kwd-group>
<kwd>autophagy</kwd>
<kwd>angiogenesis</kwd>
<kwd>multiple myeloma</kwd>
<kwd>plasma cells</kwd>
<kwd>endothelial cells</kwd>
<kwd>drug resistance</kwd>
<kwd>bortezomib</kwd>
</kwd-group>
</article-meta>
</front>
<body>
<sec sec-type="intro" id="sec1-jcm-09-00552">
<title>1. Introduction</title>
<p>Multiple myeloma (MM, see
<xref rid="jcm-09-00552-t001" ref-type="table">Table 1</xref>
for a list of abbreviations and acronyms used) is a malignant proliferation of monoclonal plasma cells (PCs) with a strong tropism for bone and bone marrow. It is preceded by a preneoplastic phase, termed monoclonal gammopathy of undetermined significance (MGUS) [
<xref rid="B1-jcm-09-00552" ref-type="bibr">1</xref>
]. Among PC dyscrasias, MM is the second most frequent hematological malignancy, with 32,110 cases predicted to have occurred in the USA in 2019 [
<xref rid="B2-jcm-09-00552" ref-type="bibr">2</xref>
]. Although the majority of patients respond to initial therapy, most will ultimately suffer disease relapse due to the proliferation of resistant tumor cells [
<xref rid="B3-jcm-09-00552" ref-type="bibr">3</xref>
,
<xref rid="B4-jcm-09-00552" ref-type="bibr">4</xref>
]. However, with the recent introduction of immunomodulatory drugs and proteasome inhibitors, the prognosis of MM patients has substantially improved [
<xref rid="B5-jcm-09-00552" ref-type="bibr">5</xref>
,
<xref rid="B6-jcm-09-00552" ref-type="bibr">6</xref>
]. Bortezomib (Velcade, formerly PS-341), a reversible inhibitor of the chymotrypsin-like activity of the proteasome [
<xref rid="B7-jcm-09-00552" ref-type="bibr">7</xref>
], directly inhibits the proliferation of myeloma cells, induces their apoptosis, reverses drug resistance, and affects myeloma cell interactions with the bone marrow microenvironment by blocking cytokine circuits, cell adhesion, and angiogenesis in vivo [
<xref rid="B8-jcm-09-00552" ref-type="bibr">8</xref>
,
<xref rid="B9-jcm-09-00552" ref-type="bibr">9</xref>
,
<xref rid="B10-jcm-09-00552" ref-type="bibr">10</xref>
,
<xref rid="B11-jcm-09-00552" ref-type="bibr">11</xref>
]. The effectiveness of bortezomib in the treatment of patients with relapsed refractory MM was first demonstrated in a multicenter, open-label, nonrandomized phase 2 study [
<xref rid="B12-jcm-09-00552" ref-type="bibr">12</xref>
] and then confirmed in a large randomized phase 3 trial that compared bortezomib with high-dose dexamethasone in MM patients who relapsed after one to three other therapies [
<xref rid="B13-jcm-09-00552" ref-type="bibr">13</xref>
]. Although bortezomib is a valid alternative for MM patients, relapse due to bortezomib-resistance is inevitable and the disease, at present, remains incurable. In MM patients, each different plasma cell sub-clone mimics a tumor-initiating niche. Thus, while bortezomib eliminates bortezomib-sensitive tumor plasma cell sub-clones, it also promotes the expansion of pre-existing bortezomib-resistant sub-clones, leading to relapse [
<xref rid="B14-jcm-09-00552" ref-type="bibr">14</xref>
,
<xref rid="B15-jcm-09-00552" ref-type="bibr">15</xref>
,
<xref rid="B16-jcm-09-00552" ref-type="bibr">16</xref>
]. Consequently, the development of new therapeutic strategies, such as combination therapies, that overcome bortezomib resistance is urgently needed [
<xref rid="B17-jcm-09-00552" ref-type="bibr">17</xref>
,
<xref rid="B18-jcm-09-00552" ref-type="bibr">18</xref>
].</p>
<p>Bortezomib resistance may be mediated by the activation of the autophagy pathway, as an alternative mechanism of protein degradation [
<xref rid="B19-jcm-09-00552" ref-type="bibr">19</xref>
,
<xref rid="B20-jcm-09-00552" ref-type="bibr">20</xref>
]. Autophagy is a catabolic process that is well conserved among all mammals because it modulates homeostasis, by clearing and recycling damaged or useless cell constituents [
<xref rid="B21-jcm-09-00552" ref-type="bibr">21</xref>
]. Due to the enormous amounts of misfolded protein generated in malignant PCs, autophagy modulation becomes a pro-survival mechanism in the event of proteasomal inhibition. Previous studies demonstrated that simultaneous proteasome and autophagy inhibition results in the accumulation of ubiquitinated proteins and thus in cytotoxicity [
<xref rid="B20-jcm-09-00552" ref-type="bibr">20</xref>
,
<xref rid="B22-jcm-09-00552" ref-type="bibr">22</xref>
,
<xref rid="B23-jcm-09-00552" ref-type="bibr">23</xref>
]. Moreover, autophagy inhibition enhances the efficacy of many anticancer drugs, both in cell lines and in animal models [
<xref rid="B24-jcm-09-00552" ref-type="bibr">24</xref>
,
<xref rid="B25-jcm-09-00552" ref-type="bibr">25</xref>
,
<xref rid="B26-jcm-09-00552" ref-type="bibr">26</xref>
,
<xref rid="B27-jcm-09-00552" ref-type="bibr">27</xref>
,
<xref rid="B28-jcm-09-00552" ref-type="bibr">28</xref>
], and synergistically increases bortezomib cytotoxicity in in vitro models of myeloma [
<xref rid="B29-jcm-09-00552" ref-type="bibr">29</xref>
,
<xref rid="B30-jcm-09-00552" ref-type="bibr">30</xref>
], colon carcinoma [
<xref rid="B31-jcm-09-00552" ref-type="bibr">31</xref>
], and hepatocarcinoma [
<xref rid="B25-jcm-09-00552" ref-type="bibr">25</xref>
]. Hydroxychloroquine (HCQ) is a well-known inhibitor of autophagy [
<xref rid="B32-jcm-09-00552" ref-type="bibr">32</xref>
,
<xref rid="B33-jcm-09-00552" ref-type="bibr">33</xref>
,
<xref rid="B34-jcm-09-00552" ref-type="bibr">34</xref>
] and is commonly used to treat autoimmune diseases [
<xref rid="B35-jcm-09-00552" ref-type="bibr">35</xref>
,
<xref rid="B36-jcm-09-00552" ref-type="bibr">36</xref>
,
<xref rid="B37-jcm-09-00552" ref-type="bibr">37</xref>
]. A therapeutic strategy based on the combined targeting of proteasomal and autophagic protein degradation was investigated in a phase I trial in which 25 patients with relapsed/refractory myeloma were treated with bortezomib and HCQ [
<xref rid="B38-jcm-09-00552" ref-type="bibr">38</xref>
]. The results demonstrated that this drug combination is therapeutically feasible, well-tolerated and potentially effective in improving outcome in MM patients. Out of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease, suggesting an enhanced efficacy of the combined drugs vs. bortezomib alone [
<xref rid="B38-jcm-09-00552" ref-type="bibr">38</xref>
].</p>
<p>In the present study, we investigated the effect of bortezomib and HCQ treatment on PCs and endothelial cells (ECs) isolated from patients with MGUS and MM (
<xref ref-type="fig" rid="jcm-09-00552-f001">Figure 1</xref>
). We show that bortezomib combined with HCQ induces synergistic cytotoxicity in myeloma PCs, whereas this effect is lost on bone marrow ECs.</p>
</sec>
<sec sec-type="results" id="sec2-jcm-09-00552">
<title>2. Results</title>
<p>To determine the effects of bortezomib modulation on autophagic flux in PCs and ECs from MGUS and MM patients, we first determined the optimal HCQ concentration and treatment time to achieve total autophagy inhibition, characterized by autophagosome accumulation and pathway saturation, in both cell types. RPMI 8226 plasma cell lines, as well as ECs from MGUS (MGECs) and MM (MMECs) patients, were treated with increasing concentrations of HCQ (0.5–500 µM) for 0, 2, 4, 6, and 24 h (
<xref ref-type="app" rid="app1-jcm-09-00552">Figure S1</xref>
).</p>
<p>The autophagic flux was monitored by measuring the levels of microtubule-associated protein light chain beta (LC3B)-II and p62 on a western blot. LC3B-II is associated with both the outer and inner membranes of the autophagosome and is thus used as a marker for these organelles [
<xref rid="B39-jcm-09-00552" ref-type="bibr">39</xref>
]. p62 (also known as SQSTM1/sequestome 1) is a cytoplasmic protein that shuttles ubiquitinated proteins to autophagosomes. It is integrated into autophagosomes through direct binding to LC3B-II and is efficiently degraded by autophagy [
<xref rid="B40-jcm-09-00552" ref-type="bibr">40</xref>
]; thus, total cellular expression levels of p62 inversely correlate with autophagic activity [
<xref rid="B39-jcm-09-00552" ref-type="bibr">39</xref>
].</p>
<p>The results of the LC3B-II and p62 measurements indicated that 100 μM of HCQ was the optimal concentration and 24 h the optimal treatment time to achieve autophagy saturation. Under these conditions, LC3B-II protein levels were 6-fold higher than in the control RPMI 8226 cells (
<xref ref-type="app" rid="app1-jcm-09-00552">Figure S1A,B</xref>
), while in the former p62 levels were reduced by half (
<xref ref-type="app" rid="app1-jcm-09-00552">Figure S1A,C</xref>
).</p>
<p>In ECs treated with 100 μM HCQ for 24 h, LC3-II (membrane-bound form of LC3) levels increased 3.5-fold in both MGECs and MMECs whereas p62 levels were reduced by 60% and 80%, respectively, indicating saturation of the autophagic flux (
<xref ref-type="app" rid="app1-jcm-09-00552">Figure S1D–F</xref>
).</p>
<p>To investigate the mechanism by which bortezomib modulates the autophagic flux in PCs and ECs, bortezomib treatment was introduced after autophagic flux saturation in response to HCQ had been reached in both cell types. Thus, MM cells were treated with 10 nM bortezomib for 24 h [
<xref rid="B41-jcm-09-00552" ref-type="bibr">41</xref>
]. An increase in LC3B-II levels under saturation in response to HCQ treatment was interpreted as positive modulation of autophagic flux and a decrease in LC3B-II levels as negative modulation. Treatment of the RPMI 8226, JJN-3 plasma cell lines, and bone marrow PCs isolated from MM patients with bortezomib and HCQ resulted in a strong reduction of LC3B-II levels compared with cells treated with HCQ alone, from 3.46 ± 1.45 to 0.77 ± 0.16 in RPMI 8226 cells (
<italic>p</italic>
= 0.005) (
<xref ref-type="fig" rid="jcm-09-00552-f002">Figure 2</xref>
A,B), from 3.58 ± 0.6 to 0.69 ± 0.07 in JJN-3 cells (
<italic>p</italic>
= 0.0031) (
<xref ref-type="fig" rid="jcm-09-00552-f002">Figure 2</xref>
D,E), and from 2.63 ± 1.00 to 0.81 ± 0.36 in primary MM PCs (
<italic>p</italic>
= 0.0286) (
<xref ref-type="fig" rid="jcm-09-00552-f003">Figure 3</xref>
A,B). These observations suggested that bortezomib decreases autophagosome formation acting as a downregulator of the autophagic flux in PCs, a finding confirmed by the analysis of p62 levels. In fact, in cells treated with a combination of bortezomib and HCQ there was a strong reduction in p62 levels compared with cells treated with HCQ alone, from 0.76 ± 0.05 to 0.41 ± 0.07 (
<italic>p</italic>
= 0.0003) in RPMI 8226 cells, from 1.29 ± 0.12 to 0.84 ± 0.07 (
<italic>p</italic>
= 0.001) in JJN-3 cells (
<xref ref-type="fig" rid="jcm-09-00552-f002">Figure 2</xref>
C,F), and from 1.45 ± 0.18 to 0.81 ± 0.36 in primary MM PCs (
<italic>p</italic>
= 0.0286) (
<xref ref-type="fig" rid="jcm-09-00552-f003">Figure 3</xref>
C,D).</p>
<p>Taken together, these findings suggested that bortezomib treatment enhances the inhibition of the autophagy pathway that occurs in myeloma PCs in response to HCQ. Bortezomib downregulates the autophagic flux decreasing autophagosome formation. Thus, the additional blockade of autophagosome–lysosome fusion by HCQ determines a reduction in autophagosome accumulation. This results in a decrease of p62 levels that become lower than those observed in cells treated with HCQ alone.</p>
<p>By contrast, the opposite results were obtained in human umbilical vein endothelial cells (HUVECs) and bone marrow ECs isolated from MGUS and MM patients (
<xref ref-type="fig" rid="jcm-09-00552-f004">Figure 4</xref>
). When cells were treated with both bortezomib and HCQ, LC3B-II levels increased compared with cells treated with HCQ alone, up to 6.63 ± 0.49 (
<italic>p</italic>
= 0.003) in HUVECs (
<xref ref-type="fig" rid="jcm-09-00552-f004">Figure 4</xref>
A,B), 2.948 ± 0.57 in MGECs (
<italic>p</italic>
= 0.003), and 3.66 ± 0.62 (
<italic>p</italic>
= 0.003) in MMECs (
<xref ref-type="fig" rid="jcm-09-00552-f004">Figure 4</xref>
D,E). The effect was greater in ECs from MM patients than in those from MGUS patients, although the difference was hardly significant (
<xref ref-type="fig" rid="jcm-09-00552-f004">Figure 4</xref>
E).</p>
<p>Treatment with both drugs led to a similar increase in p62 levels, from 0.78 ± 0.08 to 1.30 ± 0.04 (
<italic>p</italic>
= 0.001) in MGECs and from 0.75 ± 0.05 to 1.31 ± 0.04 (
<italic>p</italic>
= 0.0001) in MMECs compared with cells treated with HCQ alone (
<xref ref-type="fig" rid="jcm-09-00552-f004">Figure 4</xref>
D,F). Treatment of HUVECs did not cause an increase in p62 levels (
<xref ref-type="fig" rid="jcm-09-00552-f004">Figure 4</xref>
A,C).</p>
<p>Overall, these results indicated that bortezomib stimulates autophagic flux and consequently the autophagosome formation in ECs. This effect, when combined with that of HCQ (i.e., the blockade of autophagosome–lysosome fusion), causes the accumulation of many autophagosomes along with the accumulation of p62 protein in the cytoplasm of ECs.</p>
<p>Autophagosome accumulation in the cytoplasm of ECs was then examined by conventional light microscopy (
<xref ref-type="fig" rid="jcm-09-00552-f005">Figure 5</xref>
). HUVEC, MGECs, and MMECs were treated with 10 nM bortezomib and 100 µM HCQ, either alone or in combination, for 24 h. The number and size of the autophagosomes (dark arrows) were progressively enhanced in control, bortezomib alone, HCQ alone, and combined treatment (
<xref ref-type="fig" rid="jcm-09-00552-f005">Figure 5</xref>
), indicative of the positive modulation of the autophagic pathway by bortezomib.</p>
<p>Next, we asked whether the inhibition of proteasome by bortezomib and the blockade of autophagy by HCQ affected the proliferation (and viability) of PCs and ECs in MGUS and MM patients (
<xref ref-type="fig" rid="jcm-09-00552-f006">Figure 6</xref>
). Myeloma PCs, MGECs, and MMECs were cultured in the presence of 10 nM bortezomib and 100 μM HCQ, either alone or in combination. After 24 h, proliferation was measured in a luciferin–luciferase reaction. In myeloma PCs, although bortezomib and HCQ alone inhibited proliferation compared to control cells (53.7 ± 7.06% and 35.54 ± 3.63% respectively), combination treatment caused a much stronger inhibition compared with control cells and with treatment with HCQ alone (up to 82.53 ± 6.34%;
<italic>p</italic>
= 0.0004;
<xref ref-type="fig" rid="jcm-09-00552-f006">Figure 6</xref>
A). This effect was partially lost in MGECs and MMECs (
<xref ref-type="fig" rid="jcm-09-00552-f006">Figure 6</xref>
B,C). After treatment with bortezomib and HCQ alone, proliferation was inhibited in MGECs (26.48 ± 2.93% and 35.76 ± 5.06%, respectively) (
<xref ref-type="fig" rid="jcm-09-00552-f006">Figure 6</xref>
B) and in MMECs (23.93 ± 2.6% and 30.27 ± 1.41%, respectively) (
<xref ref-type="fig" rid="jcm-09-00552-f006">Figure 6</xref>
C) with no significant differences between the treatment with HCQ alone and the treatment with both bortezomib and HCQ (
<xref ref-type="fig" rid="jcm-09-00552-f006">Figure 6</xref>
B,C).</p>
<p>Finally, we determined the cytotoxicity of the combined treatment (bortezomib and HCQ in myeloma PCs, MGECs, and MMECs cultured in the presence of 10 nM bortezomib or 100 μM HCQ alone or in the presence of both drugs). After 24 h, cell apoptosis was evaluated by flow cytometry (
<xref ref-type="fig" rid="jcm-09-00552-f007">Figure 7</xref>
). Combined treatment resulted in the enhancement of bortezomib-induced cytotoxicity in myeloma PCs and MGECs (
<xref ref-type="fig" rid="jcm-09-00552-f007">Figure 7</xref>
A,B), whereas in MMECs the percentages of early and late apoptotic cells were largely unchanged (
<xref ref-type="fig" rid="jcm-09-00552-f007">Figure 7</xref>
C).</p>
<p>Overall, these findings demonstrated that myeloma PCs are more sensitive than ECs to the simultaneous blockade of autophagy and proteasome. Moreover, MGECs were more responsive than MMECs to the combination of bortezomib and HCQ, suggesting that ECs become resistant during the progression from MGUS to MM.</p>
</sec>
<sec sec-type="discussion" id="sec3-jcm-09-00552">
<title>3. Discussion</title>
<p>Although the introduction of bortezomib as a therapeutic strategy has improved the overall survival of MM patients, from less than 3 years in the 1990s to the current rate of roughly 10 years for patients under 65 and 5–6 years for older patients [
<xref rid="B42-jcm-09-00552" ref-type="bibr">42</xref>
], 15–20% of high-risk patients do not respond to bortezomib over time or become resistant to treatment and die within 2 years after the diagnosis [
<xref rid="B42-jcm-09-00552" ref-type="bibr">42</xref>
,
<xref rid="B43-jcm-09-00552" ref-type="bibr">43</xref>
]. The efficacy of proteasome inhibitor therapy is linked to the capacity of tumor PCs to degrade unfolded/misfolded proteins in the proteasome. Myeloma PCs are characterized by reduced proteasome expression but an increased proteasome workload (likely due to immunoglobulin (Ig) synthesis) and greater apoptotic sensitivity to bortezomib [
<xref rid="B44-jcm-09-00552" ref-type="bibr">44</xref>
,
<xref rid="B45-jcm-09-00552" ref-type="bibr">45</xref>
]. In the presence of a proteasome inhibitor, a potential PC survival strategy is the activation of autophagy, an alternative cellular mechanism of protein degradation [
<xref rid="B19-jcm-09-00552" ref-type="bibr">19</xref>
]. Proteasome inhibition by bortezomib in tumor PCs results in the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER), a response referred to as ER stress, accompanied by the overproduction of reactive oxygen species in the ER, and the activation of unfolded protein cascade components, especially the protein kinase R-like (PKR-like) ER kinase, resulting in the induction of autophagy [
<xref rid="B46-jcm-09-00552" ref-type="bibr">46</xref>
]. The ER-stress-induced activation of c-Jun N-terminal kinase is another possible mechanism by which bortezomib stimulates autophagy [
<xref rid="B47-jcm-09-00552" ref-type="bibr">47</xref>
] in myeloma PCs as a prosurvival process. Therefore, simultaneously targeting proteasome and autophagy in MM should result in enhanced anti-myeloma effects. Vogl et al. demonstrated an enhanced antitumor efficacy by the combined targeting of proteasomal and autophagic protein degradation using bortezomib and HCQ in MM [
<xref rid="B38-jcm-09-00552" ref-type="bibr">38</xref>
].</p>
<p>The present study provided evidence that combined treatment with bortezomib and HCQ targets not only myeloma PCs but also bone marrow ECs responsible for tumor angiogenesis, a recognized hallmark of the MGUS-to-MM progression, associated with a poor prognosis [
<xref rid="B48-jcm-09-00552" ref-type="bibr">48</xref>
,
<xref rid="B49-jcm-09-00552" ref-type="bibr">49</xref>
]. Our results showed that bortezomib has opposite effects on autophagy in PCs and ECs. In myeloma PCs, bortezomib interacts synergistically with HCQ resulting in high ER stress levels due to the intracellular accumulation of large amounts of toxic misfolded immunoglobulins, and predisposition to apoptosis given that the threshold for apoptosis activation was pushed to lower stress levels when autophagy was downregulated [
<xref rid="B44-jcm-09-00552" ref-type="bibr">44</xref>
,
<xref rid="B50-jcm-09-00552" ref-type="bibr">50</xref>
]. Interestingly, shrank autophagy correlated with permeation of permissive immune microenvironment and infiltration of regulatory T cells [
<xref rid="B51-jcm-09-00552" ref-type="bibr">51</xref>
]. Given that bone milieu and endothelium plays a major role in MM progression and drug-resistant phenotype, actively modulating immune-microenvironment at the same time [
<xref rid="B52-jcm-09-00552" ref-type="bibr">52</xref>
], it is tempting to speculate a pivotal role of autophagy in a vicious cycle existing between tumoral myeloma PCs and the primed permissive stromal cells [
<xref rid="B53-jcm-09-00552" ref-type="bibr">53</xref>
]. In the frame of this thinking, an altered basal autophagy process could occur in myeloma PCs because of the many genetic alterations, also in a tumor microenvironment driven fashion. [
<xref rid="B54-jcm-09-00552" ref-type="bibr">54</xref>
].</p>
<p>To corroborate this hypothesis, we used the STRING database [
<xref rid="B55-jcm-09-00552" ref-type="bibr">55</xref>
,
<xref rid="B56-jcm-09-00552" ref-type="bibr">56</xref>
] to investigate ‘possible’ interactions among the major proteins involved in autophagy: LC3B-I (MAP1LC3A), LC3B-II (MAP1LC3B), and SQSTM-1 (p62), the autophagy-related (ATG) family proteins involved in autophagosome formation, and the driver mutated genes in RPMI-8226 and JJN3 myeloma cell lines, Kirsten rat sarcoma viral oncogene homolog (KRAS) and MAF1, respectively. A diagram depicting the protein–protein interactions is presented in
<xref ref-type="app" rid="app1-jcm-09-00552">Figure S2</xref>
. The gene ontology report analysis confirmed that the ATG family proteins microtubule-associated proteins 1A/1B light chain 3A (MAP1LC3A), microtubule-associated proteins 1A/1B light chain 3B or LC3 (MAP1LC3B), SQSTM-1, and Cyclin-dependent kinase inhibitor 2A (CDKN2A) are tangled in distinct autophagic processes (mitophagy, Gene Ontology (GO):0000422 and macro-autophagy, GO:0016236; blue and red sectors, respectively), in apoptosis (GO:0009267; green sectors) because of a strong connection with tumoral protein 53 (TP53) and B-cell lymphoma-2 (BCL2), and in the positive regulation of cellular metabolic processes because of interactions with TP53, BCL2, MYC, epidermal growth factor receptor 2 (EGFR2), erythroblastic oncogene B2 (ERBB2), KRAS, and MAF1 (GO:0031325, yellow sectors). Collectively, the generated protein–protein interaction analysis indicated a significant correlation between the driver oncogenomic mutation KRAS and MAF1 and abnormal basal autophagy in myeloma PCs. Therefore, these results suggest a plausible hypothesis that prompts further validation on a statistically powered study. Remarkably, abnormal basal autophagy was absent in ECs in which the effect of bortezomib contrasted with that of HCQ and resulted in an increase of the autophagic flux rather than in autophagy blockade, with evidence of increased autophagosome formation at microscopy, events associated with EC survival, and increase of proliferation. Ongoing and planned studies will further address the possibility of better elucidating and fingerprinting autophagy marker levels in a dynamic fashion to accurately assess changes during the different steps of the autophagy process in any given biological setting.</p>
<p>Overall, our data show that while combination treatment with bortezomib and HCQ significantly downregulates autophagy in myeloma PCs promoting PC death, it also positively modulates autophagy in ECs, supporting their survival. Thus, autophagy inhibitors, such as HCQ, when used in association with bortezomib, may induce this response in resistant myeloma PCs, although an anti-angiogenic drug must be included to achieve a complete remission, as the simultaneous pro-angiogenic effect could, in fact, promote the proliferation of a small residual tumor PC clone to cause relapse.</p>
<p>Accordingly, our study should be followed by further translational investigations of the role of therapeutic suppression in autophagy modulation. Statistically powered clinical studies aimed at identifying the therapeutic relevance of this biologic network will contribute to the elucidation of the drug resistance mechanisms arising from these molecular events.</p>
</sec>
<sec id="sec4-jcm-09-00552">
<title>4. Materials and Methods</title>
<sec id="sec4dot1-jcm-09-00552">
<title>4.1. Study Subjects and Biological Samples</title>
<p>Bone marrow samples were obtained from 20 patients with newly diagnosed monoclonal gammopathies. Patients were classified as having MGUS (
<italic>n</italic>
= 9) or symptomatic MM (
<italic>n</italic>
= 11) according to the International Myeloma Working Group criteria [
<xref rid="B57-jcm-09-00552" ref-type="bibr">57</xref>
]. Bone marrow sampling consisted of aspiration followed by biopsy of the posterior iliac crest. The study protocol was approved by the University of Bari Medical School Ethics Committee and conformed to the good clinical practice guidelines of the Italian Ministry of Health. Written informed consent was obtained from each patient in accordance with the Declaration of Helsinki.</p>
</sec>
<sec id="sec4dot2-jcm-09-00552">
<title>4.2. Plasma Cell Lines</title>
<p>RPMI-8226 and JJN-3 human MM cell lines and HUVECs were purchased from the ATCC. The MM cell lines were cultured in RPMI-1640 supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 100 U penicillin/mL, and 100 µg streptomycin/mL (all from Sigma-Aldrich, St. Louis, MO, USA). HUVECs were cultured in endothelial cell growth medium supplemented with 5% FBS, cytokines, and growth factors (EGM-2, Lonza, Basel, Switzerland). All cells were grown at 37 °C in a humidified atmosphere containing 5% CO
<sub>2.</sub>
</p>
</sec>
<sec id="sec4dot3-jcm-09-00552">
<title>4.3. Primary Endothelial Cell Preparation</title>
<p>Bone marrow mononuclear cells (BMMCs) were isolated by Ficoll-Paque Plus (GE Healthcare Life Sciences, Björkgatan, Sweden) density gradient centrifugation. ECs were isolated by automated magnetic cell sorting using anti-CD31 microbeads (Miltenyi Biotec, Bergisch Gladbach, Germany) from adherent BMMCs that had been cultured for 3 weeks in Dulbecco’s modified Eagle’s medium supplemented with 10% FBS, 2 mM L-glutamine, 100 U penicillin/mL, and 100 μg streptomycin/mL (all from Sigma-Aldrich). All sorted cell populations exhibited >95% purity, as determined by flow cytometry of immunostained cells. Purified ECs were grown and expanded for four passages in fibronectin-coated culture dishes (Becton Dickinson-BD, San Jose, CA, USA) in EGM-2.</p>
</sec>
<sec id="sec4dot4-jcm-09-00552">
<title>4.4. Reagents</title>
<p>Bortezomib (Velcade, Selleckchem, USA) was purchased from Selleckchem and used at a concentration of 10 nM. HCQ was purchased from Sigma-Aldrich and used at a concentration of 100 μM.</p>
</sec>
<sec id="sec4dot5-jcm-09-00552">
<title>4.5. Immunoblotting</title>
<p>ECs (5 × 10
<sup>5</sup>
) or PCs (1 × 10
<sup>6</sup>
) cultured with bortezomib and/or HCQ as previously described were harvested, washed, and lysed using radioimmunoprecipitation assay (RIPA) lysis buffer (Sigma-Aldrich, St. Louis, Missouri, USA) supplemented with protease inhibitors (Sigma-Aldrich, St. Louis, Missouri, USA). The cell lysates (35 μg) were subjected to SDS-PAGE and transferred to a nitrocellulose membrane (Bio-Rad, Hercules, USA). After blocking with 5% dry milk, the membrane was incubated overnight at 4 °C with anti-microtubule-associated protein 1 light chain 3 beta (LC3B; Cell Signaling, Leiden, The Netherlands), anti-sequestosome-1/ubiquitin-binding protein p62 (SQSTM1/p62; Abcam, Cambridge, United Kingdom), or anti-β-actin (Sigma-Aldrich, St. Louis, Missouri, USA) primary antibodies, followed by a washing step and a 1-h incubation with the appropriate Horseradish Peroxidase (HRP)-conjugated secondary antibody. ECL detection was performed using the Clarity™Western ECL blotting substrate (BioRad, Hercules, USA) and subsequent quantification with the ChemiDoc™ XRS+ system (Image Lab™ Software) (Biorad, Hercules, USA).</p>
</sec>
<sec id="sec4dot6-jcm-09-00552">
<title>4.6. Cytotoxicity Assay</title>
<p>PCs (2 × 10
<sup>4</sup>
) or immunomagnetically purified ECs (1.5 × 10
<sup>4</sup>
) were cultured in 96-well round plates in the presence of bortezomib (0.5–1000 nM) and/or HCQ (0.5–500 µM) for 2, 4, 6, and 24 h. The cells were grown in 200 μL of RPMI-1640 or EGM-2 medium at 37 °C in a humidified atmosphere containing 5% CO
<sub>2</sub>
. Cytotoxicity was determined using the CellTiter-Glo
<sup>®</sup>
luminescent cell viability assay kit (Promega, Woods Hollow Road Madison, USA). The luminescence signal was detected using a VICTOR multilabel plate reader.</p>
</sec>
<sec id="sec4dot7-jcm-09-00552">
<title>4.7. Apoptosis Assay</title>
<p>PCs (3 × 10
<sup>5</sup>
) or ECs (5 × 10
<sup>5</sup>
) were cultured in 60-mm dishes alone or in the presence of 10 nM bortezomib and/or 100 μM HCQ. After 24 h, the cells were harvested, washed once with 1 × Annexin V binding buffer, incubated with 7-ADD and PE-Annexin V (all from Becton Dickinson-BD, San Jose, CA, USA), and immediately analyzed by flow cytometry using an FC500 flow cytometer and CXP software (Beckman Coulter, USA).</p>
</sec>
<sec id="sec4dot8-jcm-09-00552">
<title>4.8. Protein–Protein Interaction Analysis</title>
<p>Gene ontology analysis was performed by uploading peptides involved in the autophagy pathway to the Search Tool for the Retrieval of Interacting Genes (STRING) (
<uri xlink:href="http://string-db.org">http://string-db.org</uri>
) (D. Szklarczyk D561).</p>
</sec>
<sec id="sec4dot9-jcm-09-00552">
<title>4.9. Statistical Analysis</title>
<p>Statistical analyses were performed using Prism (GraphPad Software, San Diego, CA, USA). Parametric statistics were applicable because of the normally distributed data. Tests included an unpaired
<italic>t</italic>
-test for the comparisons of groups.
<italic>p</italic>
-values are shown only for statistically significant comparisons. A
<italic>p</italic>
value < 0.05 was considered to indicate statistical significance.</p>
</sec>
</sec>
</body>
<back>
<app-group>
<app id="app1-jcm-09-00552">
<title>Supplementary Materials</title>
<p>The following are available online at
<uri xlink:href="https://www.mdpi.com/2077-0383/9/2/552/s1">https://www.mdpi.com/2077-0383/9/2/552/s1</uri>
, Figure S1: Autophagy saturation with HCQ in PCs, MGECs and MMECs; Figure S2: Protein-protein interaction network obtained from STRING database.</p>
<supplementary-material content-type="local-data" id="jcm-09-00552-s001">
<media xlink:href="jcm-09-00552-s001.pdf">
<caption>
<p>Click here for additional data file.</p>
</caption>
</media>
</supplementary-material>
</app>
</app-group>
<notes>
<title>Author Contributions</title>
<p>Conceptualization, G.D.L., P.L., A.G.S., and V.R.; data curation, G.D.L., A.G.S., A.B., I.S., R.R., P.D., N.S., and L.C.; funding acquisition, V.R.; supervision, A.V. and V.R.; writing–original draft, G.D.L. and P.L.; writing–review and editing, P.L. and A.G.S. All authors reviewed the manuscript, approved the draft submission, and accept responsibility for all aspects of this study. All authors have read and agree to the published version of the manuscript.</p>
</notes>
<notes>
<title>Funding</title>
<p>This work was supported by the Italian Association for Cancer Research (AIRC) through an Investigator Grant (no. 20441 to VR) and by Fondo di Sviluppo e Coesione 2007-2013—APQ Ricerca Regione Puglia “Programma regionale a sostegno della specializzazione intelligente e della sostenibilità sociale ed ambientale—FutureInResearch”. This research project was also supported in part by the Apulian Regional Project “Medicina di Precisione” to AGS. The sponsors of this study are public or nonprofit organizations that support science in general; they had no role in gathering, analyzing, or interpreting the data.</p>
</notes>
<notes notes-type="COI-statement">
<title>Conflicts of Interest</title>
<p>The authors have no financial conflicts of interest.</p>
</notes>
<ref-list>
<title>References</title>
<ref id="B1-jcm-09-00552">
<label>1.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Kyle</surname>
<given-names>R.A.</given-names>
</name>
<name>
<surname>Rajkumar</surname>
<given-names>S.V.</given-names>
</name>
</person-group>
<article-title>Multiple myeloma</article-title>
<source>Blood</source>
<year>2008</year>
<volume>111</volume>
<fpage>2962</fpage>
<lpage>2972</lpage>
<pub-id pub-id-type="doi">10.1182/blood-2007-10-078022</pub-id>
<pub-id pub-id-type="pmid">18332230</pub-id>
</element-citation>
</ref>
<ref id="B2-jcm-09-00552">
<label>2.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Siegel</surname>
<given-names>R.L.</given-names>
</name>
<name>
<surname>Miller</surname>
<given-names>K.D.</given-names>
</name>
<name>
<surname>Jemal</surname>
<given-names>A.</given-names>
</name>
</person-group>
<article-title>Cancer statistics, 2019</article-title>
<source>CA Cancer J. Clin.</source>
<year>2019</year>
<volume>69</volume>
<fpage>7</fpage>
<lpage>34</lpage>
<pub-id pub-id-type="doi">10.3322/caac.21551</pub-id>
<pub-id pub-id-type="pmid">30620402</pub-id>
</element-citation>
</ref>
<ref id="B3-jcm-09-00552">
<label>3.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Laubach</surname>
<given-names>J.P.</given-names>
</name>
<name>
<surname>Voorhees</surname>
<given-names>P.M.</given-names>
</name>
<name>
<surname>Hassoun</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Jakubowiak</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Lonial</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Richardson</surname>
<given-names>P.G.</given-names>
</name>
</person-group>
<article-title>Current strategies for treatment of relapsed/refractory multiple myeloma</article-title>
<source>Expert Rev. Hematol.</source>
<year>2014</year>
<volume>7</volume>
<fpage>97</fpage>
<lpage>111</lpage>
<pub-id pub-id-type="doi">10.1586/17474086.2014.882764</pub-id>
<pub-id pub-id-type="pmid">24471924</pub-id>
</element-citation>
</ref>
<ref id="B4-jcm-09-00552">
<label>4.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Yang</surname>
<given-names>W.C.</given-names>
</name>
<name>
<surname>Lin</surname>
<given-names>S.F.</given-names>
</name>
</person-group>
<article-title>Mechanisms of Drug Resistance in Relapse and Refractory Multiple Myeloma</article-title>
<source>BioMed Res. Int.</source>
<year>2015</year>
<volume>2015</volume>
<fpage>341430</fpage>
<pub-id pub-id-type="doi">10.1155/2015/341430</pub-id>
<pub-id pub-id-type="pmid">26649299</pub-id>
</element-citation>
</ref>
<ref id="B5-jcm-09-00552">
<label>5.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Harousseau</surname>
<given-names>J.L.</given-names>
</name>
<name>
<surname>Attal</surname>
<given-names>M.</given-names>
</name>
</person-group>
<article-title>How I treat first relapse of myeloma</article-title>
<source>Blood</source>
<year>2017</year>
<volume>130</volume>
<fpage>963</fpage>
<lpage>973</lpage>
<pub-id pub-id-type="doi">10.1182/blood-2017-03-726703</pub-id>
<pub-id pub-id-type="pmid">28679737</pub-id>
</element-citation>
</ref>
<ref id="B6-jcm-09-00552">
<label>6.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Laubach</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Garderet</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Mahindra</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Gahrton</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Caers</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Sezer</surname>
<given-names>O.</given-names>
</name>
<name>
<surname>Voorhees</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Leleu</surname>
<given-names>X.</given-names>
</name>
<name>
<surname>Johnsen</surname>
<given-names>H.E.</given-names>
</name>
<name>
<surname>Streetly</surname>
<given-names>M.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Management of relapsed multiple myeloma: Recommendations of the International Myeloma Working Group</article-title>
<source>Leukemia</source>
<year>2016</year>
<volume>30</volume>
<fpage>1005</fpage>
<lpage>1017</lpage>
<pub-id pub-id-type="doi">10.1038/leu.2015.356</pub-id>
<pub-id pub-id-type="pmid">26710887</pub-id>
</element-citation>
</ref>
<ref id="B7-jcm-09-00552">
<label>7.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Adams</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Palombella</surname>
<given-names>V.J.</given-names>
</name>
<name>
<surname>Sausville</surname>
<given-names>E.A.</given-names>
</name>
<name>
<surname>Johnson</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Destree</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Lazarus</surname>
<given-names>D.D.</given-names>
</name>
<name>
<surname>Maas</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Pien</surname>
<given-names>C.S.</given-names>
</name>
<name>
<surname>Prakash</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Elliott</surname>
<given-names>P.J.</given-names>
</name>
</person-group>
<article-title>Proteasome inhibitors: A novel class of potent and effective antitumor agents</article-title>
<source>Cancer Res.</source>
<year>1999</year>
<volume>59</volume>
<fpage>2615</fpage>
<lpage>2622</lpage>
<pub-id pub-id-type="pmid">10363983</pub-id>
</element-citation>
</ref>
<ref id="B8-jcm-09-00552">
<label>8.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hideshima</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Mitsiades</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Akiyama</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Hayashi</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Chauhan</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Richardson</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Schlossman</surname>
<given-names>R.</given-names>
</name>
<name>
<surname>Podar</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Munshi</surname>
<given-names>N.C.</given-names>
</name>
<name>
<surname>Mitsiades</surname>
<given-names>N.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341</article-title>
<source>Blood</source>
<year>2003</year>
<volume>101</volume>
<fpage>1530</fpage>
<lpage>1534</lpage>
<pub-id pub-id-type="doi">10.1182/blood-2002-08-2543</pub-id>
<pub-id pub-id-type="pmid">12393500</pub-id>
</element-citation>
</ref>
<ref id="B9-jcm-09-00552">
<label>9.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hideshima</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Richardson</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Chauhan</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Palombella</surname>
<given-names>V.J.</given-names>
</name>
<name>
<surname>Elliott</surname>
<given-names>P.J.</given-names>
</name>
<name>
<surname>Adams</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Anderson</surname>
<given-names>K.C.</given-names>
</name>
</person-group>
<article-title>The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells</article-title>
<source>Cancer Res.</source>
<year>2001</year>
<volume>61</volume>
<fpage>3071</fpage>
<lpage>3076</lpage>
<pub-id pub-id-type="pmid">11306489</pub-id>
</element-citation>
</ref>
<ref id="B10-jcm-09-00552">
<label>10.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>LeBlanc</surname>
<given-names>R.</given-names>
</name>
<name>
<surname>Catley</surname>
<given-names>L.P.</given-names>
</name>
<name>
<surname>Hideshima</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Lentzsch</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Mitsiades</surname>
<given-names>C.S.</given-names>
</name>
<name>
<surname>Mitsiades</surname>
<given-names>N.</given-names>
</name>
<name>
<surname>Neuberg</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Goloubeva</surname>
<given-names>O.</given-names>
</name>
<name>
<surname>Pien</surname>
<given-names>C.S.</given-names>
</name>
<name>
<surname>Adams</surname>
<given-names>J.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model</article-title>
<source>Cancer Res.</source>
<year>2002</year>
<volume>62</volume>
<fpage>4996</fpage>
<lpage>5000</lpage>
<pub-id pub-id-type="pmid">12208752</pub-id>
</element-citation>
</ref>
<ref id="B11-jcm-09-00552">
<label>11.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Mitsiades</surname>
<given-names>N.</given-names>
</name>
<name>
<surname>Mitsiades</surname>
<given-names>C.S.</given-names>
</name>
<name>
<surname>Poulaki</surname>
<given-names>V.</given-names>
</name>
<name>
<surname>Chauhan</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Fanourakis</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Gu</surname>
<given-names>X.</given-names>
</name>
<name>
<surname>Bailey</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Joseph</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Libermann</surname>
<given-names>T.A.</given-names>
</name>
<name>
<surname>Treon</surname>
<given-names>S.P.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Molecular sequelae of proteasome inhibition in human multiple myeloma cells</article-title>
<source>Proc. Natl. Acad. Sci. USA</source>
<year>2002</year>
<volume>99</volume>
<fpage>14374</fpage>
<lpage>14379</lpage>
<pub-id pub-id-type="doi">10.1073/pnas.202445099</pub-id>
<pub-id pub-id-type="pmid">12391322</pub-id>
</element-citation>
</ref>
<ref id="B12-jcm-09-00552">
<label>12.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Richardson</surname>
<given-names>P.G.</given-names>
</name>
<name>
<surname>Barlogie</surname>
<given-names>B.</given-names>
</name>
<name>
<surname>Berenson</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Singhal</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Jagannath</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Irwin</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Rajkumar</surname>
<given-names>S.V.</given-names>
</name>
<name>
<surname>Srkalovic</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Alsina</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Alexanian</surname>
<given-names>R.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>A phase 2 study of bortezomib in relapsed, refractory myeloma</article-title>
<source>N. Engl. J. Med.</source>
<year>2003</year>
<volume>348</volume>
<fpage>2609</fpage>
<lpage>2617</lpage>
<pub-id pub-id-type="doi">10.1056/NEJMoa030288</pub-id>
<pub-id pub-id-type="pmid">12826635</pub-id>
</element-citation>
</ref>
<ref id="B13-jcm-09-00552">
<label>13.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Richardson</surname>
<given-names>P.G.</given-names>
</name>
<name>
<surname>Sonneveld</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Schuster</surname>
<given-names>M.W.</given-names>
</name>
<name>
<surname>Irwin</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Stadtmauer</surname>
<given-names>E.A.</given-names>
</name>
<name>
<surname>Facon</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Harousseau</surname>
<given-names>J.L.</given-names>
</name>
<name>
<surname>Ben-Yehuda</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Lonial</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Goldschmidt</surname>
<given-names>H.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Bortezomib or high-dose dexamethasone for relapsed multiple myeloma</article-title>
<source>N. Engl. J. Med.</source>
<year>2005</year>
<volume>352</volume>
<fpage>2487</fpage>
<lpage>2498</lpage>
<pub-id pub-id-type="doi">10.1056/NEJMoa043445</pub-id>
<pub-id pub-id-type="pmid">15958804</pub-id>
</element-citation>
</ref>
<ref id="B14-jcm-09-00552">
<label>14.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Egan</surname>
<given-names>J.B.</given-names>
</name>
<name>
<surname>Shi</surname>
<given-names>C.X.</given-names>
</name>
<name>
<surname>Tembe</surname>
<given-names>W.</given-names>
</name>
<name>
<surname>Christoforides</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Kurdoglu</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Sinari</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Middha</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Asmann</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Schmidt</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Braggio</surname>
<given-names>E.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides</article-title>
<source>Blood</source>
<year>2012</year>
<volume>120</volume>
<fpage>1060</fpage>
<lpage>1066</lpage>
<pub-id pub-id-type="doi">10.1182/blood-2012-01-405977</pub-id>
<pub-id pub-id-type="pmid">22529291</pub-id>
</element-citation>
</ref>
<ref id="B15-jcm-09-00552">
<label>15.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Keats</surname>
<given-names>J.J.</given-names>
</name>
<name>
<surname>Chesi</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Egan</surname>
<given-names>J.B.</given-names>
</name>
<name>
<surname>Garbitt</surname>
<given-names>V.M.</given-names>
</name>
<name>
<surname>Palmer</surname>
<given-names>S.E.</given-names>
</name>
<name>
<surname>Braggio</surname>
<given-names>E.</given-names>
</name>
<name>
<surname>Van Wier</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Blackburn</surname>
<given-names>P.R.</given-names>
</name>
<name>
<surname>Baker</surname>
<given-names>A.S.</given-names>
</name>
<name>
<surname>Dispenzieri</surname>
<given-names>A.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Clonal competition with alternating dominance in multiple myeloma</article-title>
<source>Blood</source>
<year>2012</year>
<volume>120</volume>
<fpage>1067</fpage>
<lpage>1076</lpage>
<pub-id pub-id-type="doi">10.1182/blood-2012-01-405985</pub-id>
<pub-id pub-id-type="pmid">22498740</pub-id>
</element-citation>
</ref>
<ref id="B16-jcm-09-00552">
<label>16.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Magrangeas</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Avet-Loiseau</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Gouraud</surname>
<given-names>W.</given-names>
</name>
<name>
<surname>Lode</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Decaux</surname>
<given-names>O.</given-names>
</name>
<name>
<surname>Godmer</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Garderet</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Voillat</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Facon</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Stoppa</surname>
<given-names>A.M.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Minor clone provides a reservoir for relapse in multiple myeloma</article-title>
<source>Leukemia</source>
<year>2013</year>
<volume>27</volume>
<fpage>473</fpage>
<lpage>481</lpage>
<pub-id pub-id-type="doi">10.1038/leu.2012.226</pub-id>
<pub-id pub-id-type="pmid">22874878</pub-id>
</element-citation>
</ref>
<ref id="B17-jcm-09-00552">
<label>17.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Boudreault</surname>
<given-names>J.S.</given-names>
</name>
<name>
<surname>Touzeau</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Moreau</surname>
<given-names>P.</given-names>
</name>
</person-group>
<article-title>Triplet combinations in relapsed/refractory myeloma: Update on recent phase 3 trials</article-title>
<source>Expert Rev. Hematol.</source>
<year>2017</year>
<volume>10</volume>
<fpage>207</fpage>
<lpage>215</lpage>
<pub-id pub-id-type="doi">10.1080/17474086.2017.1285694</pub-id>
<pub-id pub-id-type="pmid">28110581</pub-id>
</element-citation>
</ref>
<ref id="B18-jcm-09-00552">
<label>18.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chhabra</surname>
<given-names>S.</given-names>
</name>
</person-group>
<article-title>Novel Proteasome Inhibitors and Histone Deacetylase Inhibitors: Progress in Myeloma Therapeutics</article-title>
<source>Pharmaceuticals (Basel)</source>
<year>2017</year>
<volume>10</volume>
<pub-id pub-id-type="doi">10.3390/ph10020040</pub-id>
</element-citation>
</ref>
<ref id="B19-jcm-09-00552">
<label>19.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Desantis</surname>
<given-names>V.</given-names>
</name>
<name>
<surname>Saltarella</surname>
<given-names>I.</given-names>
</name>
<name>
<surname>Lamanuzzi</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Mariggio</surname>
<given-names>M.A.</given-names>
</name>
<name>
<surname>Racanelli</surname>
<given-names>V.</given-names>
</name>
<name>
<surname>Vacca</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Frassanito</surname>
<given-names>M.A.</given-names>
</name>
</person-group>
<article-title>Autophagy: A New Mechanism of Prosurvival and Drug Resistance in Multiple Myeloma</article-title>
<source>Transl. Oncol.</source>
<year>2018</year>
<volume>11</volume>
<fpage>1350</fpage>
<lpage>1357</lpage>
<pub-id pub-id-type="doi">10.1016/j.tranon.2018.08.014</pub-id>
<pub-id pub-id-type="pmid">30196237</pub-id>
</element-citation>
</ref>
<ref id="B20-jcm-09-00552">
<label>20.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ding</surname>
<given-names>W.X.</given-names>
</name>
<name>
<surname>Ni</surname>
<given-names>H.M.</given-names>
</name>
<name>
<surname>Gao</surname>
<given-names>W.</given-names>
</name>
<name>
<surname>Yoshimori</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Stolz</surname>
<given-names>D.B.</given-names>
</name>
<name>
<surname>Ron</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Yin</surname>
<given-names>X.M.</given-names>
</name>
</person-group>
<article-title>Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability</article-title>
<source>Am. J. Pathol.</source>
<year>2007</year>
<volume>171</volume>
<fpage>513</fpage>
<lpage>524</lpage>
<pub-id pub-id-type="doi">10.2353/ajpath.2007.070188</pub-id>
<pub-id pub-id-type="pmid">17620365</pub-id>
</element-citation>
</ref>
<ref id="B21-jcm-09-00552">
<label>21.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Li</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Wang</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Hu</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Sheng</surname>
<given-names>R.</given-names>
</name>
</person-group>
<article-title>Autophagy regulators as potential cancer therapeutic agents: A review</article-title>
<source>Curr. Top. Med. Chem.</source>
<year>2015</year>
<volume>15</volume>
<fpage>720</fpage>
<lpage>744</lpage>
<pub-id pub-id-type="doi">10.2174/1568026615666150302105343</pub-id>
<pub-id pub-id-type="pmid">25732790</pub-id>
</element-citation>
</ref>
<ref id="B22-jcm-09-00552">
<label>22.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Frassanito</surname>
<given-names>M.A.</given-names>
</name>
<name>
<surname>De Veirman</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Desantis</surname>
<given-names>V.</given-names>
</name>
<name>
<surname>Di Marzo</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Vergara</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Ruggieri</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Annese</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Nico</surname>
<given-names>B.</given-names>
</name>
<name>
<surname>Menu</surname>
<given-names>E.</given-names>
</name>
<name>
<surname>Catacchio</surname>
<given-names>I.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Halting pro-survival autophagy by TGFbeta inhibition in bone marrow fibroblasts overcomes bortezomib resistance in multiple myeloma patients</article-title>
<source>Leukemia</source>
<year>2016</year>
<volume>30</volume>
<fpage>640</fpage>
<lpage>648</lpage>
<pub-id pub-id-type="doi">10.1038/leu.2015.289</pub-id>
<pub-id pub-id-type="pmid">26487273</pub-id>
</element-citation>
</ref>
<ref id="B23-jcm-09-00552">
<label>23.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hideshima</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Bradner</surname>
<given-names>J.E.</given-names>
</name>
<name>
<surname>Wong</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Chauhan</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Richardson</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Schreiber</surname>
<given-names>S.L.</given-names>
</name>
<name>
<surname>Anderson</surname>
<given-names>K.C.</given-names>
</name>
</person-group>
<article-title>Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma</article-title>
<source>Proc. Natl. Acad. Sci. USA</source>
<year>2005</year>
<volume>102</volume>
<fpage>8567</fpage>
<lpage>8572</lpage>
<pub-id pub-id-type="doi">10.1073/pnas.0503221102</pub-id>
<pub-id pub-id-type="pmid">15937109</pub-id>
</element-citation>
</ref>
<ref id="B24-jcm-09-00552">
<label>24.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Amaravadi</surname>
<given-names>R.K.</given-names>
</name>
<name>
<surname>Lippincott-Schwartz</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Yin</surname>
<given-names>X.M.</given-names>
</name>
<name>
<surname>Weiss</surname>
<given-names>W.A.</given-names>
</name>
<name>
<surname>Takebe</surname>
<given-names>N.</given-names>
</name>
<name>
<surname>Timmer</surname>
<given-names>W.</given-names>
</name>
<name>
<surname>DiPaola</surname>
<given-names>R.S.</given-names>
</name>
<name>
<surname>Lotze</surname>
<given-names>M.T.</given-names>
</name>
<name>
<surname>White</surname>
<given-names>E.</given-names>
</name>
</person-group>
<article-title>Principles and current strategies for targeting autophagy for cancer treatment</article-title>
<source>Clin. Cancer Res.</source>
<year>2011</year>
<volume>17</volume>
<fpage>654</fpage>
<lpage>666</lpage>
<pub-id pub-id-type="doi">10.1158/1078-0432.CCR-10-2634</pub-id>
<pub-id pub-id-type="pmid">21325294</pub-id>
</element-citation>
</ref>
<ref id="B25-jcm-09-00552">
<label>25.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hui</surname>
<given-names>B.</given-names>
</name>
<name>
<surname>Shi</surname>
<given-names>Y.H.</given-names>
</name>
<name>
<surname>Ding</surname>
<given-names>Z.B.</given-names>
</name>
<name>
<surname>Zhou</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Gu</surname>
<given-names>C.Y.</given-names>
</name>
<name>
<surname>Peng</surname>
<given-names>Y.F.</given-names>
</name>
<name>
<surname>Yang</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Liu</surname>
<given-names>W.R.</given-names>
</name>
<name>
<surname>Shi</surname>
<given-names>G.M.</given-names>
</name>
<name>
<surname>Fan</surname>
<given-names>J.</given-names>
</name>
</person-group>
<article-title>Proteasome inhibitor interacts synergistically with autophagy inhibitor to suppress proliferation and induce apoptosis in hepatocellular carcinoma</article-title>
<source>Cancer</source>
<year>2012</year>
<volume>118</volume>
<fpage>5560</fpage>
<lpage>5571</lpage>
<pub-id pub-id-type="doi">10.1002/cncr.27586</pub-id>
<pub-id pub-id-type="pmid">22517429</pub-id>
</element-citation>
</ref>
<ref id="B26-jcm-09-00552">
<label>26.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Jia</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Gopinathan</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Sukumar</surname>
<given-names>J.T.</given-names>
</name>
<name>
<surname>Gribben</surname>
<given-names>J.G.</given-names>
</name>
</person-group>
<article-title>Blocking autophagy prevents bortezomib-induced NF-kappaB activation by reducing I-kappaBalpha degradation in lymphoma cells</article-title>
<source>PLoS ONE</source>
<year>2012</year>
<volume>7</volume>
<elocation-id>e32584</elocation-id>
<pub-id pub-id-type="doi">10.1371/journal.pone.0032584</pub-id>
<pub-id pub-id-type="pmid">22393418</pub-id>
</element-citation>
</ref>
<ref id="B27-jcm-09-00552">
<label>27.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Milani</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Rzymski</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Mellor</surname>
<given-names>H.R.</given-names>
</name>
<name>
<surname>Pike</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Bottini</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Generali</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Harris</surname>
<given-names>A.L.</given-names>
</name>
</person-group>
<article-title>The role of ATF4 stabilization and autophagy in resistance of breast cancer cells treated with Bortezomib</article-title>
<source>Cancer Res.</source>
<year>2009</year>
<volume>69</volume>
<fpage>4415</fpage>
<lpage>4423</lpage>
<pub-id pub-id-type="doi">10.1158/0008-5472.CAN-08-2839</pub-id>
<pub-id pub-id-type="pmid">19417138</pub-id>
</element-citation>
</ref>
<ref id="B28-jcm-09-00552">
<label>28.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Yao</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Wang</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Wei</surname>
<given-names>W.</given-names>
</name>
<name>
<surname>Tu</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Tong</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Sun</surname>
<given-names>S.</given-names>
</name>
</person-group>
<article-title>An autophagy inhibitor enhances the inhibition of cell proliferation induced by a proteasome inhibitor in MCF-7 cells</article-title>
<source>Mol. Med. Rep.</source>
<year>2012</year>
<volume>5</volume>
<fpage>84</fpage>
<lpage>88</lpage>
<pub-id pub-id-type="doi">10.3892/mmr.2011.590</pub-id>
<pub-id pub-id-type="pmid">21931937</pub-id>
</element-citation>
</ref>
<ref id="B29-jcm-09-00552">
<label>29.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Escalante</surname>
<given-names>A.M.</given-names>
</name>
<name>
<surname>McGrath</surname>
<given-names>R.T.</given-names>
</name>
<name>
<surname>Karolak</surname>
<given-names>M.R.</given-names>
</name>
<name>
<surname>Dorr</surname>
<given-names>R.T.</given-names>
</name>
<name>
<surname>Lynch</surname>
<given-names>R.M.</given-names>
</name>
<name>
<surname>Landowski</surname>
<given-names>T.H.</given-names>
</name>
</person-group>
<article-title>Preventing the autophagic survival response by inhibition of calpain enhances the cytotoxic activity of bortezomib in vitro and in vivo</article-title>
<source>Cancer Chemother. Pharmacol.</source>
<year>2013</year>
<volume>71</volume>
<fpage>1567</fpage>
<lpage>1576</lpage>
<pub-id pub-id-type="doi">10.1007/s00280-013-2156-3</pub-id>
<pub-id pub-id-type="pmid">23572175</pub-id>
</element-citation>
</ref>
<ref id="B30-jcm-09-00552">
<label>30.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Kawaguchi</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Miyazawa</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Moriya</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Ohtomo</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Che</surname>
<given-names>X.F.</given-names>
</name>
<name>
<surname>Naito</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Itoh</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Tomoda</surname>
<given-names>A.</given-names>
</name>
</person-group>
<article-title>Combined treatment with bortezomib plus bafilomycin A1 enhances the cytocidal effect and induces endoplasmic reticulum stress in U266 myeloma cells: Crosstalk among proteasome, autophagy-lysosome and ER stress</article-title>
<source>Int. J. Oncol.</source>
<year>2011</year>
<volume>38</volume>
<fpage>643</fpage>
<lpage>654</lpage>
<pub-id pub-id-type="doi">10.3892/ijo.2010.882</pub-id>
<pub-id pub-id-type="pmid">21174067</pub-id>
</element-citation>
</ref>
<ref id="B31-jcm-09-00552">
<label>31.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ding</surname>
<given-names>W.X.</given-names>
</name>
<name>
<surname>Ni</surname>
<given-names>H.M.</given-names>
</name>
<name>
<surname>Gao</surname>
<given-names>W.</given-names>
</name>
<name>
<surname>Chen</surname>
<given-names>X.</given-names>
</name>
<name>
<surname>Kang</surname>
<given-names>J.H.</given-names>
</name>
<name>
<surname>Stolz</surname>
<given-names>D.B.</given-names>
</name>
<name>
<surname>Liu</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Yin</surname>
<given-names>X.M.</given-names>
</name>
</person-group>
<article-title>Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy</article-title>
<source>Mol. Cancer. Ther.</source>
<year>2009</year>
<volume>8</volume>
<fpage>2036</fpage>
<lpage>2045</lpage>
<pub-id pub-id-type="doi">10.1158/1535-7163.MCT-08-1169</pub-id>
<pub-id pub-id-type="pmid">19584239</pub-id>
</element-citation>
</ref>
<ref id="B32-jcm-09-00552">
<label>32.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Amaravadi</surname>
<given-names>R.K.</given-names>
</name>
<name>
<surname>Yu</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Lum</surname>
<given-names>J.J.</given-names>
</name>
<name>
<surname>Bui</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Christophorou</surname>
<given-names>M.A.</given-names>
</name>
<name>
<surname>Evan</surname>
<given-names>G.I.</given-names>
</name>
<name>
<surname>Thomas-Tikhonenko</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Thompson</surname>
<given-names>C.B.</given-names>
</name>
</person-group>
<article-title>Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma</article-title>
<source>J. Clin. Investig.</source>
<year>2007</year>
<volume>117</volume>
<fpage>326</fpage>
<lpage>336</lpage>
<pub-id pub-id-type="doi">10.1172/JCI28833</pub-id>
<pub-id pub-id-type="pmid">17235397</pub-id>
</element-citation>
</ref>
<ref id="B33-jcm-09-00552">
<label>33.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Frieboes</surname>
<given-names>H.B.</given-names>
</name>
<name>
<surname>Huang</surname>
<given-names>J.S.</given-names>
</name>
<name>
<surname>Yin</surname>
<given-names>W.C.</given-names>
</name>
<name>
<surname>McNally</surname>
<given-names>L.R.</given-names>
</name>
</person-group>
<article-title>Chloroquine-mediated cell death in metastatic pancreatic adenocarcinoma through inhibition of autophagy</article-title>
<source>JOP</source>
<year>2014</year>
<volume>15</volume>
<fpage>189</fpage>
<lpage>197</lpage>
<pub-id pub-id-type="doi">10.6092/1590-8577/1900</pub-id>
<pub-id pub-id-type="pmid">24618445</pub-id>
</element-citation>
</ref>
<ref id="B34-jcm-09-00552">
<label>34.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Long</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Yang</surname>
<given-names>X.</given-names>
</name>
<name>
<surname>Southwood</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Lu</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Marciniak</surname>
<given-names>S.J.</given-names>
</name>
<name>
<surname>Dunmore</surname>
<given-names>B.J.</given-names>
</name>
<name>
<surname>Morrell</surname>
<given-names>N.W.</given-names>
</name>
</person-group>
<article-title>Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type II receptor degradation</article-title>
<source>Circ. Res.</source>
<year>2013</year>
<volume>112</volume>
<fpage>1159</fpage>
<lpage>1170</lpage>
<pub-id pub-id-type="doi">10.1161/CIRCRESAHA.111.300483</pub-id>
<pub-id pub-id-type="pmid">23446737</pub-id>
</element-citation>
</ref>
<ref id="B35-jcm-09-00552">
<label>35.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Akdemir</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Heimans</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Bergstra</surname>
<given-names>S.A.</given-names>
</name>
<name>
<surname>Goekoop</surname>
<given-names>R.J.</given-names>
</name>
<name>
<surname>van Oosterhout</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>van Groenendael</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Peeters</surname>
<given-names>A.J.</given-names>
</name>
<name>
<surname>Steup-Beekman</surname>
<given-names>G.M.</given-names>
</name>
<name>
<surname>Lard</surname>
<given-names>L.R.</given-names>
</name>
<name>
<surname>de Sonnaville</surname>
<given-names>P.B.J.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Clinical and radiological outcomes of 5-year drug-free remission-steered treatment in patients with early arthritis: IMPROVED study</article-title>
<source>Ann. Rheum. Dis.</source>
<year>2018</year>
<volume>77</volume>
<fpage>111</fpage>
<lpage>118</lpage>
<pub-id pub-id-type="doi">10.1136/annrheumdis-2017-211375</pub-id>
<pub-id pub-id-type="pmid">28970207</pub-id>
</element-citation>
</ref>
<ref id="B36-jcm-09-00552">
<label>36.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hsu</surname>
<given-names>C.Y.</given-names>
</name>
<name>
<surname>Lin</surname>
<given-names>Y.S.</given-names>
</name>
<name>
<surname>Su</surname>
<given-names>Y.J.</given-names>
</name>
<name>
<surname>Lin</surname>
<given-names>H.F.</given-names>
</name>
<name>
<surname>Lin</surname>
<given-names>M.S.</given-names>
</name>
<name>
<surname>Syu</surname>
<given-names>Y.J.</given-names>
</name>
<name>
<surname>Cheng</surname>
<given-names>T.T.</given-names>
</name>
<name>
<surname>Yu</surname>
<given-names>S.F.</given-names>
</name>
<name>
<surname>Chen</surname>
<given-names>J.F.</given-names>
</name>
<name>
<surname>Chen</surname>
<given-names>T.H.</given-names>
</name>
</person-group>
<article-title>Effect of long-term hydroxychloroquine on vascular events in patients with systemic lupus erythematosus: A database prospective cohort study</article-title>
<source>Rheumatology (Oxford)</source>
<year>2017</year>
<volume>56</volume>
<fpage>2212</fpage>
<lpage>2221</lpage>
<pub-id pub-id-type="doi">10.1093/rheumatology/kex357</pub-id>
<pub-id pub-id-type="pmid">29029334</pub-id>
</element-citation>
</ref>
<ref id="B37-jcm-09-00552">
<label>37.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Rempenault</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Combe</surname>
<given-names>B.</given-names>
</name>
<name>
<surname>Barnetche</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Gaujoux-Viala</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Lukas</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Morel</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Hua</surname>
<given-names>C.</given-names>
</name>
</person-group>
<article-title>Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: A systematic review and meta-analysis</article-title>
<source>Ann. Rheum. Dis.</source>
<year>2018</year>
<volume>77</volume>
<fpage>98</fpage>
<lpage>103</lpage>
<pub-id pub-id-type="doi">10.1136/annrheumdis-2017-211836</pub-id>
<pub-id pub-id-type="pmid">28970215</pub-id>
</element-citation>
</ref>
<ref id="B38-jcm-09-00552">
<label>38.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Vogl</surname>
<given-names>D.T.</given-names>
</name>
<name>
<surname>Stadtmauer</surname>
<given-names>E.A.</given-names>
</name>
<name>
<surname>Tan</surname>
<given-names>K.S.</given-names>
</name>
<name>
<surname>Heitjan</surname>
<given-names>D.F.</given-names>
</name>
<name>
<surname>Davis</surname>
<given-names>L.E.</given-names>
</name>
<name>
<surname>Pontiggia</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Rangwala</surname>
<given-names>R.</given-names>
</name>
<name>
<surname>Piao</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Chang</surname>
<given-names>Y.C.</given-names>
</name>
<name>
<surname>Scott</surname>
<given-names>E.C.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Combined autophagy and proteasome inhibition: A phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma</article-title>
<source>Autophagy</source>
<year>2014</year>
<volume>10</volume>
<fpage>1380</fpage>
<lpage>1390</lpage>
<pub-id pub-id-type="doi">10.4161/auto.29264</pub-id>
<pub-id pub-id-type="pmid">24991834</pub-id>
</element-citation>
</ref>
<ref id="B39-jcm-09-00552">
<label>39.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Mizushima</surname>
<given-names>N.</given-names>
</name>
<name>
<surname>Yoshimori</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Levine</surname>
<given-names>B.</given-names>
</name>
</person-group>
<article-title>Methods in mammalian autophagy research</article-title>
<source>Cell</source>
<year>2010</year>
<volume>140</volume>
<fpage>313</fpage>
<lpage>326</lpage>
<pub-id pub-id-type="doi">10.1016/j.cell.2010.01.028</pub-id>
<pub-id pub-id-type="pmid">20144757</pub-id>
</element-citation>
</ref>
<ref id="B40-jcm-09-00552">
<label>40.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Bjorkoy</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Lamark</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Pankiv</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Overvatn</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Brech</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Johansen</surname>
<given-names>T.</given-names>
</name>
</person-group>
<article-title>Monitoring autophagic degradation of p62/SQSTM1</article-title>
<source>Methods Enzymol.</source>
<year>2009</year>
<volume>452</volume>
<fpage>181</fpage>
<lpage>197</lpage>
<pub-id pub-id-type="doi">10.1016/S0076-6879(08)03612-4</pub-id>
<pub-id pub-id-type="pmid">19200883</pub-id>
</element-citation>
</ref>
<ref id="B41-jcm-09-00552">
<label>41.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Roccaro</surname>
<given-names>A.M.</given-names>
</name>
<name>
<surname>Hideshima</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Raje</surname>
<given-names>N.</given-names>
</name>
<name>
<surname>Kumar</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Ishitsuka</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Yasui</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Shiraishi</surname>
<given-names>N.</given-names>
</name>
<name>
<surname>Ribatti</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Nico</surname>
<given-names>B.</given-names>
</name>
<name>
<surname>Vacca</surname>
<given-names>A.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells</article-title>
<source>Cancer Res.</source>
<year>2006</year>
<volume>66</volume>
<fpage>184</fpage>
<lpage>191</lpage>
<pub-id pub-id-type="doi">10.1158/0008-5472.CAN-05-1195</pub-id>
<pub-id pub-id-type="pmid">16397231</pub-id>
</element-citation>
</ref>
<ref id="B42-jcm-09-00552">
<label>42.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Avet-Loiseau</surname>
<given-names>H.</given-names>
</name>
</person-group>
<article-title>Ultra high-risk myeloma</article-title>
<source>Hematol. Am. Soc. Hematol. Educ. Program.</source>
<year>2010</year>
<volume>2010</volume>
<fpage>489</fpage>
<lpage>493</lpage>
<pub-id pub-id-type="doi">10.1182/asheducation-2010.1.489</pub-id>
</element-citation>
</ref>
<ref id="B43-jcm-09-00552">
<label>43.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Jarauta</surname>
<given-names>V.</given-names>
</name>
<name>
<surname>Jaime</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Gonzalo</surname>
<given-names>O.</given-names>
</name>
<name>
<surname>de Miguel</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Ramirez-Labrada</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Martinez-Lostao</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Anel</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Pardo</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Marzo</surname>
<given-names>I.</given-names>
</name>
<name>
<surname>Naval</surname>
<given-names>J.</given-names>
</name>
</person-group>
<article-title>Inhibition of autophagy with chloroquine potentiates carfilzomib-induced apoptosis in myeloma cells in vitro and in vivo</article-title>
<source>Cancer Lett.</source>
<year>2016</year>
<volume>382</volume>
<fpage>1</fpage>
<lpage>10</lpage>
<pub-id pub-id-type="doi">10.1016/j.canlet.2016.08.019</pub-id>
<pub-id pub-id-type="pmid">27565383</pub-id>
</element-citation>
</ref>
<ref id="B44-jcm-09-00552">
<label>44.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Bianchi</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Oliva</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Cascio</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Pengo</surname>
<given-names>N.</given-names>
</name>
<name>
<surname>Fontana</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Cerruti</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Orsi</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Pasqualetto</surname>
<given-names>E.</given-names>
</name>
<name>
<surname>Mezghrani</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Calbi</surname>
<given-names>V.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition</article-title>
<source>Blood</source>
<year>2009</year>
<volume>113</volume>
<fpage>3040</fpage>
<lpage>3049</lpage>
<pub-id pub-id-type="doi">10.1182/blood-2008-08-172734</pub-id>
<pub-id pub-id-type="pmid">19164601</pub-id>
</element-citation>
</ref>
<ref id="B45-jcm-09-00552">
<label>45.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Racanelli</surname>
<given-names>V.</given-names>
</name>
<name>
<surname>Leone</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Frassanito</surname>
<given-names>M.A.</given-names>
</name>
<name>
<surname>Brunetti</surname>
<given-names>C.</given-names>
</name>
<name>
<surname>Perosa</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Ferrone</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Dammacco</surname>
<given-names>F.</given-names>
</name>
</person-group>
<article-title>Alterations in the antigen processing-presenting machinery of transformed plasma cells are associated with reduced recognition by CD8+ T cells and characterize the progression of MGUS to multiple myeloma</article-title>
<source>Blood</source>
<year>2010</year>
<volume>115</volume>
<fpage>1185</fpage>
<lpage>1193</lpage>
<pub-id pub-id-type="doi">10.1182/blood-2009-06-228676</pub-id>
<pub-id pub-id-type="pmid">20008301</pub-id>
</element-citation>
</ref>
<ref id="B46-jcm-09-00552">
<label>46.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Kouroku</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Fujita</surname>
<given-names>E.</given-names>
</name>
<name>
<surname>Tanida</surname>
<given-names>I.</given-names>
</name>
<name>
<surname>Ueno</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Isoai</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Kumagai</surname>
<given-names>H.</given-names>
</name>
<name>
<surname>Ogawa</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Kaufman</surname>
<given-names>R.J.</given-names>
</name>
<name>
<surname>Kominami</surname>
<given-names>E.</given-names>
</name>
<name>
<surname>Momoi</surname>
<given-names>T.</given-names>
</name>
</person-group>
<article-title>ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation</article-title>
<source>Cell Death Differ.</source>
<year>2007</year>
<volume>14</volume>
<fpage>230</fpage>
<lpage>239</lpage>
<pub-id pub-id-type="doi">10.1038/sj.cdd.4401984</pub-id>
<pub-id pub-id-type="pmid">16794605</pub-id>
</element-citation>
</ref>
<ref id="B47-jcm-09-00552">
<label>47.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ogata</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Hino</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Saito</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Morikawa</surname>
<given-names>K.</given-names>
</name>
<name>
<surname>Kondo</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Kanemoto</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Murakami</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Taniguchi</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Tanii</surname>
<given-names>I.</given-names>
</name>
<name>
<surname>Yoshinaga</surname>
<given-names>K.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Autophagy is activated for cell survival after endoplasmic reticulum stress</article-title>
<source>Mol. Cell. Biol.</source>
<year>2006</year>
<volume>26</volume>
<fpage>9220</fpage>
<lpage>9231</lpage>
<pub-id pub-id-type="doi">10.1128/MCB.01453-06</pub-id>
<pub-id pub-id-type="pmid">17030611</pub-id>
</element-citation>
</ref>
<ref id="B48-jcm-09-00552">
<label>48.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Kawano</surname>
<given-names>Y.</given-names>
</name>
<name>
<surname>Moschetta</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Manier</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Glavey</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Gorgun</surname>
<given-names>G.T.</given-names>
</name>
<name>
<surname>Roccaro</surname>
<given-names>A.M.</given-names>
</name>
<name>
<surname>Anderson</surname>
<given-names>K.C.</given-names>
</name>
<name>
<surname>Ghobrial</surname>
<given-names>I.M.</given-names>
</name>
</person-group>
<article-title>Targeting the bone marrow microenvironment in multiple myeloma</article-title>
<source>Immunol. Rev.</source>
<year>2015</year>
<volume>263</volume>
<fpage>160</fpage>
<lpage>172</lpage>
<pub-id pub-id-type="doi">10.1111/imr.12233</pub-id>
<pub-id pub-id-type="pmid">25510276</pub-id>
</element-citation>
</ref>
<ref id="B49-jcm-09-00552">
<label>49.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ribatti</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Vacca</surname>
<given-names>A.</given-names>
</name>
</person-group>
<article-title>New Insights in Anti-Angiogenesis in Multiple Myeloma</article-title>
<source>Int. J. Mol. Sci.</source>
<year>2018</year>
<volume>19</volume>
<pub-id pub-id-type="doi">10.3390/ijms19072031</pub-id>
</element-citation>
</ref>
<ref id="B50-jcm-09-00552">
<label>50.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Holczer</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Marton</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Kurucz</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Banhegyi</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Kapuy</surname>
<given-names>O.</given-names>
</name>
</person-group>
<article-title>A Comprehensive Systems Biological Study of Autophagy-Apoptosis Crosstalk during Endoplasmic Reticulum Stress</article-title>
<source>BioMed Res. Int.</source>
<year>2015</year>
<volume>2015</volume>
<fpage>319589</fpage>
<pub-id pub-id-type="doi">10.1155/2015/319589</pub-id>
<pub-id pub-id-type="pmid">25984530</pub-id>
</element-citation>
</ref>
<ref id="B51-jcm-09-00552">
<label>51.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Rao</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Tortola</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Perlot</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Wirnsberger</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Novatchkova</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Nitsch</surname>
<given-names>R.</given-names>
</name>
<name>
<surname>Sykacek</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Frank</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Schramek</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Komnenovic</surname>
<given-names>V.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>A dual role for autophagy in a murine model of lung cancer</article-title>
<source>Nat. Commun.</source>
<year>2014</year>
<volume>5</volume>
<fpage>3056</fpage>
<pub-id pub-id-type="doi">10.1038/ncomms4056</pub-id>
<pub-id pub-id-type="pmid">24445999</pub-id>
</element-citation>
</ref>
<ref id="B52-jcm-09-00552">
<label>52.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Leone</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Di Lernia</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Solimando</surname>
<given-names>A.G.</given-names>
</name>
<name>
<surname>Cicco</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Saltarella</surname>
<given-names>I.</given-names>
</name>
<name>
<surname>Lamanuzzi</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Ria</surname>
<given-names>R.</given-names>
</name>
<name>
<surname>Frassanito</surname>
<given-names>M.A.</given-names>
</name>
<name>
<surname>Ponzoni</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Ditonno</surname>
<given-names>P.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Bone marrow endothelial cells sustain a tumor-specific CD8(+) T cell subset with suppressive function in myeloma patients</article-title>
<source>Oncoimmunology</source>
<year>2019</year>
<volume>8</volume>
<pub-id pub-id-type="doi">10.1080/2162402X.2018.1486949</pub-id>
</element-citation>
</ref>
<ref id="B53-jcm-09-00552">
<label>53.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Frassanito</surname>
<given-names>M.A.</given-names>
</name>
<name>
<surname>Desantis</surname>
<given-names>V.</given-names>
</name>
<name>
<surname>Di Marzo</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Craparotta</surname>
<given-names>I.</given-names>
</name>
<name>
<surname>Beltrame</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Marchini</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Annese</surname>
<given-names>T.</given-names>
</name>
<name>
<surname>Visino</surname>
<given-names>F.</given-names>
</name>
<name>
<surname>Arciuli</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Saltarella</surname>
<given-names>I.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Bone marrow fibroblasts overexpress miR-27b and miR-214 in step with multiple myeloma progression, dependent on tumour cell-derived exosomes</article-title>
<source>J. Pathol.</source>
<year>2019</year>
<volume>247</volume>
<fpage>241</fpage>
<lpage>253</lpage>
<pub-id pub-id-type="doi">10.1002/path.5187</pub-id>
<pub-id pub-id-type="pmid">30357841</pub-id>
</element-citation>
</ref>
<ref id="B54-jcm-09-00552">
<label>54.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Solimando</surname>
<given-names>A.G.</given-names>
</name>
<name>
<surname>Da Via</surname>
<given-names>M.C.</given-names>
</name>
<name>
<surname>Cicco</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Leone</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Di Lernia</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Giannico</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Desantis</surname>
<given-names>V.</given-names>
</name>
<name>
<surname>Frassanito</surname>
<given-names>M.A.</given-names>
</name>
<name>
<surname>Morizio</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Delgado Tascon</surname>
<given-names>J.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>High-Risk Multiple Myeloma: Integrated Clinical and Omics Approach Dissects the Neoplastic Clone and the Tumor Microenvironment</article-title>
<source>J. Clin. Med.</source>
<year>2019</year>
<volume>8</volume>
<pub-id pub-id-type="doi">10.3390/jcm8070997</pub-id>
<pub-id pub-id-type="pmid">31323969</pub-id>
</element-citation>
</ref>
<ref id="B55-jcm-09-00552">
<label>55.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Snel</surname>
<given-names>B.</given-names>
</name>
<name>
<surname>Lehmann</surname>
<given-names>G.</given-names>
</name>
<name>
<surname>Bork</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Huynen</surname>
<given-names>M.A.</given-names>
</name>
</person-group>
<article-title>STRING: A web-server to retrieve and display the repeatedly occurring neighbourhood of a gene</article-title>
<source>Nucleic Acids Res.</source>
<year>2000</year>
<volume>28</volume>
<fpage>3442</fpage>
<lpage>3444</lpage>
<pub-id pub-id-type="doi">10.1093/nar/28.18.3442</pub-id>
<pub-id pub-id-type="pmid">10982861</pub-id>
</element-citation>
</ref>
<ref id="B56-jcm-09-00552">
<label>56.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Szklarczyk</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Gable</surname>
<given-names>A.L.</given-names>
</name>
<name>
<surname>Lyon</surname>
<given-names>D.</given-names>
</name>
<name>
<surname>Junge</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Wyder</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Huerta-Cepas</surname>
<given-names>J.</given-names>
</name>
<name>
<surname>Simonovic</surname>
<given-names>M.</given-names>
</name>
<name>
<surname>Doncheva</surname>
<given-names>N.T.</given-names>
</name>
<name>
<surname>Morris</surname>
<given-names>J.H.</given-names>
</name>
<name>
<surname>Bork</surname>
<given-names>P.</given-names>
</name>
<etal></etal>
</person-group>
<article-title>STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets</article-title>
<source>Nucleic Acids Res.</source>
<year>2019</year>
<volume>47</volume>
<fpage>D607</fpage>
<lpage>D613</lpage>
<pub-id pub-id-type="doi">10.1093/nar/gky1131</pub-id>
<pub-id pub-id-type="pmid">30476243</pub-id>
</element-citation>
</ref>
<ref id="B57-jcm-09-00552">
<label>57.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<collab>International Myeloma Working Group</collab>
</person-group>
<article-title>Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: A report of the International Myeloma Working Group</article-title>
<source>Br. J. Haematol.</source>
<year>2003</year>
<volume>121</volume>
<fpage>749</fpage>
<lpage>757</lpage>
<pub-id pub-id-type="doi">10.1046/j.1365-2141.2003.04355.x</pub-id>
<pub-id pub-id-type="pmid">12780789</pub-id>
</element-citation>
</ref>
</ref-list>
</back>
<floats-group>
<fig id="jcm-09-00552-f001" orientation="portrait" position="float">
<label>Figure 1</label>
<caption>
<p>Schematic overview of the experimental design. Cytoplasmic cargo material including mitochondria, membrane, and unfolded proteins is engulfed by a double-membrane vesicle to form and elongate into an autophagosome. Autophagy related (ATG) proteins create two “ubiquitin-like conjugation systems” that catalyze the conversion of LC3B-I to its phosphatidylethanolamine (PE)-conjugated LC3B-II form. LC3B-II protein is recruited to the autophagosome and P62 along with the attached ubiquitinated proteins bind to LC3B-II protein. The complex LC3B-II-p62 is then incorporated into the autophagosome membrane, where it serves as a docking site of adaptor proteins and bound cargo. The mature autophagosome then fuses with the lysosome and forms an autolysosome, leading to cargo degradation and recycling of nutrients and metabolites. Hydroxychloroquine inhibits autophagosome–lysosome fusion and degradation. Thus, HCQ treatment promotes intracellular autophagosome accumulation that correlates with LC3B-II and p62 levels.</p>
</caption>
<graphic xlink:href="jcm-09-00552-g001"></graphic>
</fig>
<fig id="jcm-09-00552-f002" orientation="portrait" position="float">
<label>Figure 2</label>
<caption>
<p>Bortezomib and hydroxychloroquine combination decreases autophagosome formation acting as a downregulator of autophagic flux in plasma cells (PCs). RPMI 8226 (
<bold>A</bold>
) and JJN-3 (
<bold>D</bold>
) cells were treated with or without bortezomib (10 nM), hydroxychloroquine (HCQ, 100 uM), or with both drugs for 24 h, followed by immunoblotting analysis to determine LC3B-II and p62 expression levels under each condition. Densitometric analysis of RPMI 8226 (
<bold>B</bold>
,
<bold>C</bold>
) and JJN-3 (
<bold>E</bold>
,
<bold>F</bold>
) lysates for LC3B-II (
<bold>B</bold>
,
<bold>E</bold>
) and p62 (
<bold>C</bold>
,
<bold>F</bold>
) expression. The results are expressed as fold-change normalized to the β-actin level and relative to the control. Mann–Whitney U test.</p>
</caption>
<graphic xlink:href="jcm-09-00552-g002"></graphic>
</fig>
<fig id="jcm-09-00552-f003" orientation="portrait" position="float">
<label>Figure 3</label>
<caption>
<p>Bortezomib and hydroxychloroquine combination downregulates the autophagic flux in plasma cells (PCs). Changes in LC3B-II and p62 levels upon treatment with hydroxychloroquine (HCQ, 100 uM) alone or both bortezomib (10 nM) and HCQ for 24 h, determined by flow cytometry. Mean Fluorescence intensity (
<bold>A</bold>
,
<bold>C</bold>
) and representative plots (
<bold>B</bold>
,
<bold>D</bold>
) of primary plasma cells isolated from MM patients (
<italic>n</italic>
= 6). Mann–Whitney U test.</p>
</caption>
<graphic xlink:href="jcm-09-00552-g003"></graphic>
</fig>
<fig id="jcm-09-00552-f004" orientation="portrait" position="float">
<label>Figure 4</label>
<caption>
<p>Bortezomib and hydroxychloroquine combination upregulates autophagosome formation in endothelial cells (ECs). (
<bold>A</bold>
) Human umbilical vein endothelial cells (HUVECs), (
<bold>D</bold>
) ECs from monoclonal gammopathy of undetermined significance (MGECs,
<italic>n</italic>
= 9) and ECs from multiple myeloma (MMECs,
<italic>n</italic>
= 11) were treated with or without bortezomib (10 nM), HCQ (100 uM), or with both drugs for 24 h, followed by immunoblotting to determine LC3B-II and p62 levels under each condition. (
<bold>B</bold>
–
<bold>F</bold>
) Densitometric analysis of HUVEC (
<bold>B</bold>
,
<bold>C</bold>
), MGEC (black bars), and MMEC (gray bars) (
<bold>E</bold>
,
<bold>F</bold>
) lysates for LC3B-II (
<bold>B</bold>
,
<bold>E</bold>
) and p62 (
<bold>C</bold>
,
<bold>F</bold>
) expression. The results are expressed as fold-change normalized to the β-actin level and relative to the control. Mann–Whitney U test.</p>
</caption>
<graphic xlink:href="jcm-09-00552-g004"></graphic>
</fig>
<fig id="jcm-09-00552-f005" orientation="portrait" position="float">
<label>Figure 5</label>
<caption>
<p>Bortezomib and hydroxychloroquine combination increases autophagosome number in ECs. (
<bold>A</bold>
) HUVECs, MGECs (
<italic>n</italic>
= 4), and MMECs (
<italic>n</italic>
= 4) were treated with HCQ (100 uM), bortezomib (10 nM), or both drugs. Representative photomicrographs (on the left) and flow cytometry plots (on the right) of four independent experiments are shown. Black arrows indicate autophagosome vacuoles (magnification 20×).</p>
</caption>
<graphic xlink:href="jcm-09-00552-g005"></graphic>
</fig>
<fig id="jcm-09-00552-f006" orientation="portrait" position="float">
<label>Figure 6</label>
<caption>
<p>Bortezomib and HCQ differentially modulate MM cell proliferation. RPMI 8226 cells (
<bold>A</bold>
), MGECs (
<italic>n</italic>
= 6) (
<bold>B</bold>
), and MMECs (
<italic>n</italic>
= 6) (
<bold>C</bold>
) were treated with or without bortezomib (10 nM), HCQ (100 uM) or with both drugs for 24 h, after which the inhibition of proliferation was evaluated by measuring cell viability. Mann–Whitney U test. ns = not significant.</p>
</caption>
<graphic xlink:href="jcm-09-00552-g006"></graphic>
</fig>
<fig id="jcm-09-00552-f007" orientation="portrait" position="float">
<label>Figure 7</label>
<caption>
<p>Effect of combination treatment with bortezomib and HCQ on cell cytotoxicity. Representative flow cytometry plots show changes in cytotoxicity for (
<bold>A</bold>
) RPMI 8226 cells, (
<bold>B</bold>
) MGECs (
<italic>n</italic>
= 9), and (
<bold>C</bold>
) MMECs (
<italic>n</italic>
= 11) treated with or without bortezomib (10 nM), HCQ (100 uM), or with both drugs for 24 h.</p>
</caption>
<graphic xlink:href="jcm-09-00552-g007"></graphic>
</fig>
<table-wrap id="jcm-09-00552-t001" orientation="portrait" position="float">
<object-id pub-id-type="pii">jcm-09-00552-t001_Table 1</object-id>
<label>Table 1</label>
<caption>
<p>Abbreviations and acronyms.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Abbreviation</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Full Form and Definition</th>
</tr>
</thead>
<tbody>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">MM</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Multiple myeloma</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">MGUS</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Monoclonal gammopathy of undetermined significance</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">PCs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Plasma cells</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">HCQ</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Hydroxychloroquine</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">ECs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Endothelial cells</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">MGECs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Endothelial cells from MGUS patients</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">MMECs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Endothelial cells from MM patients</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">BMMCs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Bone marrow mononuclear cells</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">ATG</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Autophagy related</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">MAP1LC3A</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Microtubule-associated proteins 1A/1B light chain 3A</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">MAP1LC3B</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Microtubule-associated proteins 1A/1B light chain 3B or LC3</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">LC3B</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Microtubule-associated protein light chain beta</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">LC3-I</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Cytosolic form of LC3</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">LC3-II</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Membrane-bound form of LC3, phosphatidylethanolamine conjugated</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">RPMI 8226</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Human myeloma cell line</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">JJN3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Human myeloma cell line</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">HUVECs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Human umbilical vein endothelial cells</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">ER</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Endoplasmic reticulum</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">PKR-like</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Protein kinase R-like</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">STRING</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Biological database and web resource of known and predicted protein–protein interactions</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">SQSTM-1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Sequestosome-1 also known as p62</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">KRAS</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Kirsten rat sarcoma viral oncogene homolog</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">MAF1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Repressor of RNA polymerase III transcription</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">CDKN2A</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Cyclin-dependent kinase Inhibitor 2A</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">TP53</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Tumoral protein 53</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">BCL2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">B-cell lymphoma 2. Apoptosis regulator</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">MYC</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Family of regulator genes and proto-oncogenes that code for transcription factors</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">EGFR2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Epidermal growth factor receptor 2</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">ERBB2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Erythroblastic oncogene B2. Receptor tyrosine kinase</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">RAF-1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Proto-oncogene, serine/threonine kinase</td>
</tr>
</tbody>
</table>
</table-wrap>
</floats-group>
</pmc>
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