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dc.contributor.authorChaturvedi, Anuhar
dc.contributor.authorGupta, Charu
dc.contributor.authorGabdoulline, Razif
dc.contributor.authorBorchert, Nora M
dc.contributor.authorGoparaju, Ramya
dc.contributor.authorKaulfuss, Stefan
dc.contributor.authorGörlich, Kerstin
dc.contributor.authorSchottmann, Renate
dc.contributor.authorOthman, Basem
dc.contributor.authorWelzenbach, Julia
dc.contributor.authorPanknin, Olaf
dc.contributor.authorWagner, Markus
dc.contributor.authorGeffers, Robert
dc.contributor.authorGanser, Arnold
dc.contributor.authorThol, Felicitas
dc.contributor.authorJeffers, Michael
dc.contributor.authorHaegebarth, Andrea
dc.contributor.authorHeuser, Michael
dc.date.accessioned2020-05-28T11:38:09Z
dc.date.available2020-05-28T11:38:09Z
dc.date.issued2020-04-02
dc.identifier.citationHaematologica. 2020;haematol.2019.236992. doi:10.3324/haematol.2019.236992.en_US
dc.identifier.pmid32241846
dc.identifier.doi10.3324/haematol.2019.236992
dc.identifier.urihttp://hdl.handle.net/10033/622278
dc.description.abstractMutant IDH1 (mIDH1) inhibitors have shown single-agent activity in relapsed/refractory AML, though most patients eventually relapse. We evaluated the efficacy and molecular mechanism of the combination treatment with azacitidine, which is currently the standard of care in older AML patients, and mIDH1 inhibitor BAY1436032. Both compounds were evaluated in vivo as single agents and in combination with sequential (azacitidine, followed by BAY1436032) or simultaneous application in two human IDH1 mutated AML xenograft models. Combination treatment significantly prolonged survival compared to single agent or control treatment (P<.005). The sequential combination treatment depleted leukemia stem cells (LSC) by 470-fold. Interestingly, the simultaneous combination treatment depleted LSCs by 33,150-fold compared to control mice. This strong synergy is mediated through inhibition of MAPK/ERK and RB/E2F signaling. Our data strongly argues for the concurrent application of mIDH1 inhibitors and azacitidine and predicts improved outcome of this regimen in IDH1 mutated AML patients.en_US
dc.language.isoenen_US
dc.publisherFerrraata Storti Foundationen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectAcute Myeloid Leukemiaen_US
dc.subjectIsocitrate dehydrogenaseen_US
dc.subjectLeukemic Stem Cellen_US
dc.subjectMAPKen_US
dc.subjectMolecular Pharmacologyen_US
dc.titleSynergistic activity of IDH1 inhibitor BAY1436032 with azacitidine in IDH1 mutant acute myeloid leukemia.en_US
dc.typeArticleen_US
dc.identifier.eissn1592-8721
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalHaematologicaen_US
refterms.dateFOA2020-05-28T11:38:09Z
dc.source.journaltitleHaematologica
dc.source.countryItaly


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