Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia
作者： Irène Baccelli , Yves Gareau , Bernhard Lehnertz , Stéphane Gingras , Jean-François Spinella
DOI: 10.1016/J.CCELL.2019.06.003
关键词:
摘要: Summary To identify therapeutic targets in acute myeloid leukemia (AML), we chemically interrogated 200 sequenced primary specimens. Mubritinib, a known ERBB2 inhibitor, elicited strong anti-leukemic effects in vitro and in vivo. In the context of AML, mubritinib functions through ubiquinone-dependent inhibition electron transport chain (ETC) complex I activity. Resistance to characterized normal CD34+ hematopoietic cells chemotherapy-sensitive AMLs, which displayed transcriptomic hallmarks hypoxia. Conversely, sensitivity correlated with mitochondrial function-related gene expression levels large subset chemotherapy-resistant AMLs oxidative phosphorylation (OXPHOS) hyperactivity. Altogether, our work thus identifies an ETC inhibitor reveals genetic landscape OXPHOS dependency AML.
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