Chan Steven M, Thomas Daniel, Corces-Zimmerman M Ryan, Xavy Seethu, Rastogi Suchita, Hong Wan-Jen, Zhao Feifei, Medeiros Bruno C, Tyvoll David A, Majeti Ravindra
1] Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. [2] Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
Nat Med. 2015 Feb;21(2):178-84. doi: 10.1038/nm.3788. Epub 2015 Jan 19.
Mutant isocitrate dehydrogenase (IDH) 1 and 2 proteins alter the epigenetic landscape in acute myeloid leukemia (AML) cells through production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). Here we performed a large-scale RNA interference (RNAi) screen to identify genes that are synthetic lethal to the IDH1(R132H) mutation in AML and identified the anti-apoptotic gene BCL-2. IDH1- and IDH2-mutant primary human AML cells were more sensitive than IDH1/2 wild-type cells to ABT-199, a highly specific BCL-2 inhibitor that is currently in clinical trials for hematologic malignancies, both ex vivo and in xenotransplant models. This sensitization effect was induced by (R)-2-HG-mediated inhibition of the activity of cytochrome c oxidase (COX) in the mitochondrial electron transport chain (ETC); suppression of COX activity lowered the mitochondrial threshold to trigger apoptosis upon BCL-2 inhibition. Our findings indicate that IDH1/2 mutation status may identify patients that are likely to respond to pharmacologic BCL-2 inhibition and form the rational basis for combining agents that disrupt ETC activity with ABT-199 in future clinical studies.
突变型异柠檬酸脱氢酶（IDH）1和2蛋白通过产生致癌代谢物（R）-2-羟基戊二酸（2-HG）改变急性髓系白血病（AML）细胞的表观遗传格局。在此，我们进行了大规模RNA干扰（RNAi）筛选，以鉴定对AML中IDH1（R132H）突变具有合成致死性的基因，并鉴定出抗凋亡基因BCL-2。IDH1和IDH2突变的原发性人类AML细胞比IDH1/2野生型细胞对ABT-199更敏感，ABT-199是一种高度特异性的BCL-2抑制剂，目前正在进行血液系统恶性肿瘤的临床试验，在体外和异种移植模型中均如此。这种致敏作用是由（R）-2-HG介导的线粒体电子传递链（ETC）中细胞色素c氧化酶（COX）活性抑制所诱导的；COX活性的抑制降低了线粒体阈值，从而在BCL-2抑制时触发细胞凋亡。我们的研究结果表明，IDH1/2突变状态可能有助于识别可能对BCL-2药物抑制有反应的患者，并为未来临床研究中将破坏ETC活性的药物与ABT-199联合使用提供合理依据。
