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STAT5-and hypoxia-dependent upregulation of AXL

dc.rights.licenseopenen_US
hal.structure.identifierBiothérapies des maladies génétiques et cancers
dc.contributor.authorDUMAS, Pierre-Yves
dc.contributor.authorNAUDIN, Cécile
dc.contributor.authorMARTIN-LANNERÉE, Séverine
dc.contributor.authorIZAC, Brigitte
dc.contributor.authorCASETTI, Luana
hal.structure.identifierBiologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases
dc.contributor.authorMANSIER, Olivier
dc.contributor.authorROUSSEAU, Benoît
dc.contributor.authorARTUS, Alexandre
dc.contributor.authorDUFOSSÉE, Mélody
dc.contributor.authorGIESE, Alban
dc.contributor.authorDUBUS, Pierre
dc.contributor.authorPIGNEUX, Arnaud
dc.contributor.authorPRALORAN, Vincent
dc.contributor.authorBIDET, Audrey
dc.contributor.authorVILLACRECES, Arnaud
dc.contributor.authorGUITART, Amélie
dc.contributor.authorMILPIED, Noël
dc.contributor.authorKOSMIDER, Olivier
dc.contributor.authorVIGON, Isabelle
dc.contributor.authorDESPLAT, Vanessa
dc.contributor.authorDUSANTER-FOURT, Isabelle
dc.contributor.authorPASQUET, Jean-Max
dc.date.accessioned2020-11-16T12:01:53Z
dc.date.available2020-11-16T12:01:53Z
dc.date.issued2019-10
dc.identifier.issn0390-6078, 1592-8721en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/14025
dc.description.abstractEnInternal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones.
dc.language.isoENen_US
dc.rightsAttribution-NonCommercial 3.0 United States
dc.rights.urihttp://creativecommons.org/licenses/by-nc/3.0/us/
dc.subjectArticle RECHERCHE
dc.title.enSTAT5-and hypoxia-dependent upregulation of AXL
dc.typeArticle de revueen_US
dc.identifier.doi10.3324/haematol.2018.205385en_US
dc.subject.halSciences du Vivant [q-bio]/Médecine humaine et pathologieen_US
bordeaux.journalHaematologicaen_US
bordeaux.page2017–2027en_US
bordeaux.volume104en_US
bordeaux.hal.laboratoriesBiologie des maladies cardiovasculaires - U1034en_US
bordeaux.issue10en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.exportfalse
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Haematologica&rft.date=2019-10&rft.volume=104&rft.issue=10&rft.spage=2017%E2%80%932027&rft.epage=2017%E2%80%932027&rft.eissn=0390-6078,%201592-8721&rft.issn=0390-6078,%201592-8721&rft.au=DUMAS,%20Pierre-Yves&NAUDIN,%20C%C3%A9cile&MARTIN-LANNER%C3%89E,%20S%C3%A9verine&IZAC,%20Brigitte&CASETTI,%20Luana&rft.genre=article


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