Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia
Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia
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DOI：
10.1016/j.ccell.2019.06.003
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发表时间：
2019-07-08
期刊：
影响因子：
50.3
通讯作者：
Sauvageau, Guy
中科院分区：
文献类型：
--
作者：
Baccelli, Irene;Gareau, Yves;Sauvageau, Guy
为了确定急性髓性白血病（AML）的治疗靶点，我们对200例测序的原发性标本进行了化学询问。Mubritinib是一种已知的ERBB2抑制剂，在体外和体内均引起强烈的抗白血病作用。在AML背景下，mubritinib通过电子传递链（ETC）复合物I活性的泛醌依赖性抑制发挥作用。对mubritinib耐药的特征是正常的CD34（+）造血细胞和化疗敏感的AML，表现出缺氧的转录组学标志。相反，敏感性与线粒体功能相关的基因表达水平相关，其特征是具有氧化磷酸化（OXPHOS）活性亢进的化疗耐药AML的一个大子集。总之，我们的工作因此确定了ETC复合物I抑制剂，并揭示了AML中OXPHOS依赖性的遗传景观。
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 of electron transport chain (ETC) complex I activity. Resistance to mubritinib characterized normal CD34(+) hematopoietic cells and chemotherapy-sensitive AMLs, which displayed transcriptomic hallmarks of hypoxia. Conversely, sensitivity correlated with mitochondrial function-related gene expression levels and characterized a large subset of chemotherapy-resistant AMLs with oxidative phosphorylation (OXPHOS) hyperactivity. Altogether, our work thus identifies an ETC complex I inhibitor and reveals the genetic landscape of OXPHOS dependency in AML.