Oncogenic KIT mutations induce STAT3-dependent autophagy to support cell proliferation in acute myeloid leukemia
Identifieur interne : 000575 ( Main/Exploration ); précédent : 000574; suivant : 000576Oncogenic KIT mutations induce STAT3-dependent autophagy to support cell proliferation in acute myeloid leukemia
Auteurs : Clément Larrue [France] ; Quentin Heydt [France] ; Estelle Saland [France] ; Héléna Boutzen [France] ; Tony Kaoma [Luxembourg (pays)] ; Jean-Emmanuel Sarry [France] ; Carine Joffre [France] ; Christian Récher [France]Source :
- Oncogenesis [ 2157-9024 ] ; 2019.
Abstract
Autophagy is associated with both survival and cell death in myeloid malignancies. Therefore, deciphering its role in different genetically defined subtypes of acute myeloid leukemia (AML) is critical. Activating mutations of the KIT receptor tyrosine kinase are frequently detected in core-binding factor AML and are associated with a greater risk of relapse. Herein, we report that basal autophagy was significantly increased by the
Url:
DOI: 10.1038/s41389-019-0148-9
PubMed: 31311917
PubMed Central: 6635375
Affiliations:
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Health,</institution></institution-wrap>Strassen, Luxembourg</nlm:aff><country xml:lang="fr">Luxembourg (pays)</country><wicri:regionArea>Strassen</wicri:regionArea></affiliation></author><author><name sortKey="Sarry, Jean Emmanuel" sort="Sarry, Jean Emmanuel" uniqKey="Sarry J" first="Jean-Emmanuel" last="Sarry">Jean-Emmanuel Sarry</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.468186.5</institution-id><institution>Cancer Research Center of Toulouse (CRCT), UMR1037 INSERM, ERL5294 CNRS, Equipe Labellisée LIGUE,</institution></institution-wrap>Toulouse, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Toulouse</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2353 1689</institution-id><institution-id institution-id-type="GRID">grid.11417.32</institution-id><institution>University of Toulouse,</institution></institution-wrap>Toulouse, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Toulouse</wicri:regionArea></affiliation></author><author><name sortKey="Joffre, Carine" sort="Joffre, Carine" uniqKey="Joffre C" first="Carine" last="Joffre">Carine Joffre</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.468186.5</institution-id><institution>Cancer Research Center of Toulouse (CRCT), UMR1037 INSERM, ERL5294 CNRS, Equipe Labellisée LIGUE,</institution></institution-wrap>Toulouse, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Toulouse</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2353 1689</institution-id><institution-id institution-id-type="GRID">grid.11417.32</institution-id><institution>University of Toulouse,</institution></institution-wrap>Toulouse, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Toulouse</wicri:regionArea></affiliation></author><author><name sortKey="Recher, Christian" sort="Recher, Christian" uniqKey="Recher C" first="Christian" last="Récher">Christian Récher</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.468186.5</institution-id><institution>Cancer Research Center of Toulouse (CRCT), UMR1037 INSERM, ERL5294 CNRS, Equipe Labellisée LIGUE,</institution></institution-wrap>Toulouse, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Toulouse</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2353 1689</institution-id><institution-id institution-id-type="GRID">grid.11417.32</institution-id><institution>University of Toulouse,</institution></institution-wrap>Toulouse, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Toulouse</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="GRID">grid.488470.7</institution-id><institution>Service d’Hématologie, Centre Hospitalier Universitaire de Toulouse,</institution><institution>Institut Universitaire du Cancer de Toulouse Oncopole,</institution></institution-wrap>Toulouse, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Toulouse</wicri:regionArea></affiliation></author></analytic><series><title level="j">Oncogenesis</title><idno type="eISSN">2157-9024</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Autophagy is associated with both survival and cell death in myeloid malignancies. Therefore, deciphering its role in different genetically defined subtypes of acute myeloid leukemia (AML) is critical. Activating mutations of the KIT receptor tyrosine kinase are frequently detected in core-binding factor AML and are associated with a greater risk of relapse. Herein, we report that basal autophagy was significantly increased by the <italic>KIT</italic><sup>D816V</sup> mutation in AML cells and contributed to support their cell proliferation and survival. Invalidation of the key autophagy protein Atg12 strongly reduced tumor burden and improved survival of immunocompromised NSG mice engrafted with KIT<sup>D816V</sup> TF-1 cells. Downstream of KIT<sup>D816V</sup>, STAT3, but not AKT or ERK pathways, was identified as a major regulator of autophagy. Accordingly, STAT3 pharmacological inhibition or downregulation inhibited autophagy and reduced tumor growth both in vitro and in vivo. Taken together, our results support the notion that targeting autophagy or STAT3 opens up an exploratory pathway for finding new therapeutic opportunities for patients with CBF-AML or others malignancies with <italic>KIT</italic><sup>D816V</sup> mutations.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Boya, P" uniqKey="Boya P">P Boya</name></author><author><name sortKey="Reggiori, F" uniqKey="Reggiori F">F Reggiori</name></author><author><name sortKey="Codogno, P" uniqKey="Codogno P">P Codogno</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Choi, Amk" uniqKey="Choi A">AMK Choi</name></author><author><name sortKey="Ryter, Sw" uniqKey="Ryter S">SW Ryter</name></author><author><name sortKey="Levine, B" uniqKey="Levine B">B Levine</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lorin, S" uniqKey="Lorin S">S Lorin</name></author><author><name sortKey="Hamai, A" 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first="Héléna" last="Boutzen">Héléna Boutzen</name><name sortKey="Boutzen, Helena" sort="Boutzen, Helena" uniqKey="Boutzen H" first="Héléna" last="Boutzen">Héléna Boutzen</name><name sortKey="Heydt, Quentin" sort="Heydt, Quentin" uniqKey="Heydt Q" first="Quentin" last="Heydt">Quentin Heydt</name><name sortKey="Heydt, Quentin" sort="Heydt, Quentin" uniqKey="Heydt Q" first="Quentin" last="Heydt">Quentin Heydt</name><name sortKey="Joffre, Carine" sort="Joffre, Carine" uniqKey="Joffre C" first="Carine" last="Joffre">Carine Joffre</name><name sortKey="Joffre, Carine" sort="Joffre, Carine" uniqKey="Joffre C" first="Carine" last="Joffre">Carine Joffre</name><name sortKey="Larrue, Clement" sort="Larrue, Clement" uniqKey="Larrue C" first="Clément" last="Larrue">Clément Larrue</name><name sortKey="Recher, Christian" sort="Recher, Christian" uniqKey="Recher C" first="Christian" last="Récher">Christian Récher</name><name sortKey="Recher, Christian" sort="Recher, Christian" uniqKey="Recher C" first="Christian" last="Récher">Christian Récher</name><name sortKey="Recher, Christian" sort="Recher, Christian" uniqKey="Recher C" first="Christian" last="Récher">Christian Récher</name><name sortKey="Saland, Estelle" sort="Saland, Estelle" uniqKey="Saland E" first="Estelle" last="Saland">Estelle Saland</name><name sortKey="Saland, Estelle" sort="Saland, Estelle" uniqKey="Saland E" first="Estelle" last="Saland">Estelle Saland</name><name sortKey="Sarry, Jean Emmanuel" sort="Sarry, Jean Emmanuel" uniqKey="Sarry J" first="Jean-Emmanuel" last="Sarry">Jean-Emmanuel Sarry</name><name sortKey="Sarry, Jean Emmanuel" sort="Sarry, Jean Emmanuel" uniqKey="Sarry J" first="Jean-Emmanuel" last="Sarry">Jean-Emmanuel Sarry</name></country><country name="Luxembourg (pays)"><noRegion><name sortKey="Kaoma, Tony" sort="Kaoma, Tony" uniqKey="Kaoma T" first="Tony" last="Kaoma">Tony Kaoma</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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