Myeloid loss of Beclin 1 promotes PD-L1hi precursor B cell lymphoma development
Identifieur interne : 000B12 ( Pmc/Checkpoint ); précédent : 000B11; suivant : 000B13Myeloid loss of Beclin 1 promotes PD-L1hi precursor B cell lymphoma development
Auteurs : Peng Tan [États-Unis] ; Lian He [États-Unis] ; Changsheng Xing [États-Unis] ; Jingrong Mao [États-Unis, République populaire de Chine] ; Xiao Yu [États-Unis] ; Motao Zhu [États-Unis] ; Lixia Diao [États-Unis] ; Leng Han [États-Unis] ; Yubin Zhou [États-Unis] ; M. James You [États-Unis] ; Helen Y. Wang [États-Unis] ; Rong-Fu Wang [États-Unis]Source :
- The Journal of Clinical Investigation [ 0021-9738 ] ; ????.
Abstract
Beclin 1 (Becn1) is a key molecule in the autophagy pathway and has been implicated in cancer development. Due to the embryonic lethality of homozygous Becn1-deficient mice, the precise mechanisms and cell type–specific roles of Becn1 in regulating inflammation and cancer immunity remain elusive. Here, we report that myeloid-deficient
Url:
DOI: 10.1172/JCI127721
PubMed: 31503548
PubMed Central: 6877338
Affiliations:
- République populaire de Chine, États-Unis
- Texas, État de New York
- Ithaca (New York)
- Université Cornell
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PMC:6877338Le document en format XML
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promotes PD-L1<sup>hi</sup>
precursor B cell lymphoma development</title>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Myeloid loss of <italic>Beclin 1</italic>
promotes PD-L1<sup>hi</sup>
precursor B cell lymphoma development</title>
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<author><name sortKey="Zhu, Motao" sort="Zhu, Motao" uniqKey="Zhu M" first="Motao" last="Zhu">Motao Zhu</name>
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<author><name sortKey="Diao, Lixia" sort="Diao, Lixia" uniqKey="Diao L" first="Lixia" last="Diao">Lixia Diao</name>
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<author><name sortKey="Han, Leng" sort="Han, Leng" uniqKey="Han L" first="Leng" last="Han">Leng Han</name>
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<author><name sortKey="Zhou, Yubin" sort="Zhou, Yubin" uniqKey="Zhou Y" first="Yubin" last="Zhou">Yubin Zhou</name>
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<author><name sortKey="Wang, Helen Y" sort="Wang, Helen Y" uniqKey="Wang H" first="Helen Y." last="Wang">Helen Y. Wang</name>
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<author><name sortKey="Wang, Rong Fu" sort="Wang, Rong Fu" uniqKey="Wang R" first="Rong-Fu" last="Wang">Rong-Fu Wang</name>
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<front><div type="abstract" xml:lang="en"><p>Beclin 1 (Becn1) is a key molecule in the autophagy pathway and has been implicated in cancer development. Due to the embryonic lethality of homozygous Becn1-deficient mice, the precise mechanisms and cell type–specific roles of Becn1 in regulating inflammation and cancer immunity remain elusive. Here, we report that myeloid-deficient <italic>Becn1</italic>
(<italic>Becn1<sup>ΔM</sup>
</italic>
) mice developed neutrophilia, were hypersusceptible to LPS-induced septic shock, and had a high risk of developing spontaneous precursor B cell (pre-B cell) lymphoma with elevated expression of immunosuppressive molecules programmed death ligand 1 (PD-L1) and IL-10. <italic>Becn1</italic>
deficiency resulted in the stabilization of MEKK3 and aberrant p38 activation in neutrophils, and mediated neutrophil–B cell interaction through Cxcl9/Cxcr3 chemotaxis. Neutrophil–B cell interplay further led to the activation of IL-21/STAT3/IRF1 and CD40L/ERK signaling and PD-L1 expression; therefore, it suppressed CD8<sup>+</sup>
T cell function. Ablation of p38 in <italic>Becn1<sup>ΔM</sup>
</italic>
mice prevented neutrophil inflammation and B cell tumorigenesis. Importantly, the low expression of Becn1 in human neutrophils was significantly correlated with the PD-L1 levels in pre-B acute lymphoblastic lymphoma (ALL) patients. Our findings have identified myeloid Becn1 as a key regulator of cancer immunity and therapeutic target for pre-B cell lymphomas.</p>
</div>
</front>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Clin Invest</journal-id>
<journal-id journal-id-type="iso-abbrev">J. Clin. Invest</journal-id>
<journal-id journal-id-type="publisher-id">J Clin Invest</journal-id>
<journal-title-group><journal-title>The Journal of Clinical Investigation</journal-title>
</journal-title-group>
<issn pub-type="ppub">0021-9738</issn>
<issn pub-type="epub">1558-8238</issn>
<publisher><publisher-name>American Society for Clinical Investigation</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31503548</article-id>
<article-id pub-id-type="pmc">6877338</article-id>
<article-id pub-id-type="publisher-id">127721</article-id>
<article-id pub-id-type="doi">10.1172/JCI127721</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Myeloid loss of <italic>Beclin 1</italic>
promotes PD-L1<sup>hi</sup>
precursor B cell lymphoma development</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Tan</surname>
<given-names>Peng</given-names>
</name>
<email>ptan2@houstonmethodist.org</email>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>He</surname>
<given-names>Lian</given-names>
</name>
<email>lhe@ibt.tamhsc.edu</email>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0001-6582-9037</contrib-id>
<name><surname>Xing</surname>
<given-names>Changsheng</given-names>
</name>
<email>cxing@houstonmethodist.org</email>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mao</surname>
<given-names>Jingrong</given-names>
</name>
<email>jingrong.mao@yahoo.com</email>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Yu</surname>
<given-names>Xiao</given-names>
</name>
<email>yuxiao0626@hotmail.com</email>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhu</surname>
<given-names>Motao</given-names>
</name>
<email>mzhu@houstonmethodist.org</email>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Diao</surname>
<given-names>Lixia</given-names>
</name>
<email>ldiao@mdanderson.org</email>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0002-7380-2640</contrib-id>
<name><surname>Han</surname>
<given-names>Leng</given-names>
</name>
<email>Leng.Han@uth.tmc.edu</email>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0001-7962-0517</contrib-id>
<name><surname>Zhou</surname>
<given-names>Yubin</given-names>
</name>
<email>yzhou@ibt.tamhsc.edu</email>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>You</surname>
<given-names>M. James</given-names>
</name>
<email>mjamesyou@mdanderson.org</email>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wang</surname>
<given-names>Helen Y.</given-names>
</name>
<email>ywang4@houstonmethodist.org</email>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Wang</surname>
<given-names>Rong-Fu</given-names>
</name>
<email>rwang3@houstonmethodist.org</email>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A7">7</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas, USA.</aff>
<aff id="A2"><label>2</label>
Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas, USA.</aff>
<aff id="A3"><label>3</label>
Xiangya Hospital, Central South University, Changsha, China.</aff>
<aff id="A4"><label>4</label>
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.</aff>
<aff id="A5"><label>5</label>
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas, USA.</aff>
<aff id="A6"><label>6</label>
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.</aff>
<aff id="A7"><label>7</label>
Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, New York, USA.</aff>
<author-notes><corresp>Address correspondence to: Rong-Fu Wang, 6670 Bertner Ave, R9-460, Houston, Texas 77030, USA. Phone: 713.441.7359; Email: <email>rwang3@houstonmethodist.org</email>
.</corresp>
<fn fn-type="COI-statement"><p><bold>Conflict of interest:</bold>
The authors have declared that no conflict of interest exists.</p>
</fn>
</author-notes>
<pub-date date-type="pub" publication-format="electronic" iso-8601-date="2019-10-28T16:00:00-0400"><day>28</day>
<month>10</month>
<year>2019</year>
</pub-date>
<pub-date date-type="collection" publication-format="electronic" iso-8601-date="2019-10-28T16:00:00-0400"><day>28</day>
<month>10</month>
<year>2019</year>
</pub-date>
<pub-date date-type="pub" publication-format="print" iso-8601-date="2019-12-02T16:00:00-0500"><day>2</day>
<month>12</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>2</day>
<month>3</month>
<year>2020</year>
</pub-date>
<pmc-comment> PMC Release delay is 3 months and
0 days and was based on the . </pmc-comment>
<volume>129</volume>
<issue>12</issue>
<fpage>5261</fpage>
<lpage>5277</lpage>
<history><date date-type="received"><day>25</day>
<month>1</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>29</day>
<month>8</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© 2019 American Society for Clinical Investigation</copyright-statement>
<copyright-year>2019</copyright-year>
<copyright-holder>American Society for Clinical Investigation</copyright-holder>
</permissions>
<self-uri xlink:href="https://www.jci.org/articles/view/127721">This article is available online at https://www.jci.org/articles/view/127721</self-uri>
<abstract><p>Beclin 1 (Becn1) is a key molecule in the autophagy pathway and has been implicated in cancer development. Due to the embryonic lethality of homozygous Becn1-deficient mice, the precise mechanisms and cell type–specific roles of Becn1 in regulating inflammation and cancer immunity remain elusive. Here, we report that myeloid-deficient <italic>Becn1</italic>
(<italic>Becn1<sup>ΔM</sup>
</italic>
) mice developed neutrophilia, were hypersusceptible to LPS-induced septic shock, and had a high risk of developing spontaneous precursor B cell (pre-B cell) lymphoma with elevated expression of immunosuppressive molecules programmed death ligand 1 (PD-L1) and IL-10. <italic>Becn1</italic>
deficiency resulted in the stabilization of MEKK3 and aberrant p38 activation in neutrophils, and mediated neutrophil–B cell interaction through Cxcl9/Cxcr3 chemotaxis. Neutrophil–B cell interplay further led to the activation of IL-21/STAT3/IRF1 and CD40L/ERK signaling and PD-L1 expression; therefore, it suppressed CD8<sup>+</sup>
T cell function. Ablation of p38 in <italic>Becn1<sup>ΔM</sup>
</italic>
mice prevented neutrophil inflammation and B cell tumorigenesis. Importantly, the low expression of Becn1 in human neutrophils was significantly correlated with the PD-L1 levels in pre-B acute lymphoblastic lymphoma (ALL) patients. Our findings have identified myeloid Becn1 as a key regulator of cancer immunity and therapeutic target for pre-B cell lymphomas.</p>
</abstract>
<abstract abstract-type="graphical"><p><graphic xlink:href="jci-129-127721-g011.jpg" position="float" orientation="portrait"></graphic>
</p>
</abstract>
<kwd-group kwd-group-type="specialties"><kwd>Immunology</kwd>
<kwd>Oncology</kwd>
</kwd-group>
<kwd-group kwd-group-type="keywords"><kwd>B cells</kwd>
<kwd>Cellular immune response</kwd>
<kwd>Neutrophils</kwd>
</kwd-group>
<funding-group><award-group><funding-source><institution-wrap><institution>National Institutes of Health</institution>
<institution-id>https://doi.org/10.13039/100000002</institution-id>
</institution-wrap>
</funding-source>
<award-id>R01CA090327</award-id>
<award-id>R01CA101795</award-id>
</award-group>
<award-group><funding-source>Cancer Prevention and Research Institute of Texas</funding-source>
<award-id>RP170537</award-id>
</award-group>
<award-group><funding-source><institution-wrap><institution>U.S. Department of Defense</institution>
<institution-id>https://doi.org/10.13039/100000005</institution-id>
</institution-wrap>
</funding-source>
<award-id>W81XWH-16-1-0417</award-id>
</award-group>
</funding-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>République populaire de Chine</li>
<li>États-Unis</li>
</country>
<region><li>Texas</li>
<li>État de New York</li>
</region>
<settlement><li>Ithaca (New York)</li>
</settlement>
<orgName><li>Université Cornell</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="Texas"><name sortKey="Tan, Peng" sort="Tan, Peng" uniqKey="Tan P" first="Peng" last="Tan">Peng Tan</name>
</region>
<name sortKey="Diao, Lixia" sort="Diao, Lixia" uniqKey="Diao L" first="Lixia" last="Diao">Lixia Diao</name>
<name sortKey="Han, Leng" sort="Han, Leng" uniqKey="Han L" first="Leng" last="Han">Leng Han</name>
<name sortKey="He, Lian" sort="He, Lian" uniqKey="He L" first="Lian" last="He">Lian He</name>
<name sortKey="Mao, Jingrong" sort="Mao, Jingrong" uniqKey="Mao J" first="Jingrong" last="Mao">Jingrong Mao</name>
<name sortKey="Tan, Peng" sort="Tan, Peng" uniqKey="Tan P" first="Peng" last="Tan">Peng Tan</name>
<name sortKey="Wang, Helen Y" sort="Wang, Helen Y" uniqKey="Wang H" first="Helen Y." last="Wang">Helen Y. Wang</name>
<name sortKey="Wang, Rong Fu" sort="Wang, Rong Fu" uniqKey="Wang R" first="Rong-Fu" last="Wang">Rong-Fu Wang</name>
<name sortKey="Wang, Rong Fu" sort="Wang, Rong Fu" uniqKey="Wang R" first="Rong-Fu" last="Wang">Rong-Fu Wang</name>
<name sortKey="Wang, Rong Fu" sort="Wang, Rong Fu" uniqKey="Wang R" first="Rong-Fu" last="Wang">Rong-Fu Wang</name>
<name sortKey="Xing, Changsheng" sort="Xing, Changsheng" uniqKey="Xing C" first="Changsheng" last="Xing">Changsheng Xing</name>
<name sortKey="You, M James" sort="You, M James" uniqKey="You M" first="M. James" last="You">M. James You</name>
<name sortKey="Yu, Xiao" sort="Yu, Xiao" uniqKey="Yu X" first="Xiao" last="Yu">Xiao Yu</name>
<name sortKey="Zhou, Yubin" sort="Zhou, Yubin" uniqKey="Zhou Y" first="Yubin" last="Zhou">Yubin Zhou</name>
<name sortKey="Zhu, Motao" sort="Zhu, Motao" uniqKey="Zhu M" first="Motao" last="Zhu">Motao Zhu</name>
</country>
<country name="République populaire de Chine"><noRegion><name sortKey="Mao, Jingrong" sort="Mao, Jingrong" uniqKey="Mao J" first="Jingrong" last="Mao">Jingrong Mao</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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