Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia.
Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia.
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DOI：
10.1038/s41467-022-30223-9
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发表时间：
2022-05-12
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
生殖系变异和体细胞癌症驱动突变的相互作用正在研究中。在这里，我们描述了成人急性髓性白血病（AML）的基因组线粒体景观，并表明影响核和细胞编码的复合物I基因的罕见变异显示出与影响异柠檬酸脱氢酶1（IDH1）的体细胞驱动突变的近相互排斥性，但不是IDH2，这表明了独特的上位关系。尽管具有罕见的复合物I变体或IDH1或IDH2突变的AML细胞都显示出减弱的线粒体呼吸，但仅在IDH1突变型AML中观察到对复合物I抑制剂（包括临床级抑制剂IACS-010759）的敏感性增加。此外，对IDH1突变体抑制剂ivosidenib具有抗性的IDH1突变体母细胞保持对复合物I抑制的敏感性。我们认为IDH1突变限制了柠檬酸盐利用的灵活性，在受损的复合物I活性的存在下，IDH2突变细胞中不明显，暴露了突变特异性代谢脆弱性。这种降低的代谢可塑性解释了种系复合物I变体和致癌IDH1突变之间的上位关系，强调了基因组数据在揭示代谢脆弱性方面的效用，并对治疗产生影响。线粒体代谢与急性髓性白血病（AML）的肿瘤发生有关，目前被认为是一个潜在的治疗靶点。在这里，作者表明，在AML患者中，线粒体复合物I中的种系突变与代谢酶IDH1中的体细胞突变相互排斥，并发现IDH1突变细胞对复合物I抑制剂的敏感性增加。
The interaction of germline variation and somatic cancer driver mutations is under-investigated. Here we describe the genomic mitochondrial landscape in adult acute myeloid leukaemia (AML) and show that rare variants affecting the nuclear- and mitochondrially-encoded complex I genes show near-mutual exclusivity with somatic driver mutations affecting isocitrate dehydrogenase 1 (IDH1), but not IDH2 suggesting a unique epistatic relationship. Whereas AML cells with rare complex I variants or mutations in IDH1 or IDH2 all display attenuated mitochondrial respiration, heightened sensitivity to complex I inhibitors including the clinical-grade inhibitor, IACS-010759, is observed only for IDH1-mutant AML. Furthermore, IDH1 mutant blasts that are resistant to the IDH1-mutant inhibitor, ivosidenib, retain sensitivity to complex I inhibition. We propose that the IDH1 mutation limits the flexibility for citrate utilization in the presence of impaired complex I activity to a degree that is not apparent in IDH2 mutant cells, exposing a mutation-specific metabolic vulnerability. This reduced metabolic plasticity explains the epistatic relationship between the germline complex I variants and oncogenic IDH1 mutation underscoring the utility of genomic data in revealing metabolic vulnerabilities with implications for therapy. Mitochondrial metabolism has been associated with tumourigenesis in acute myeloid leukaemia (AML) and currently considered as a potential therapeutic target. Here, the authors show, in patients with AML, that germline mutations in mitochondrial complex I are mutually exclusive with somatic mutations in the metabolic enzyme IDH1, and find IDH1 mutant cells have increased sensitivity to complex I inhibitors.
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DOI：
10.1007/978-1-4939-7819-9_15
发表时间：
2018-01-01
期刊：
PLANT METABOLOMICS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Jayasinghe, Nirupama Samanmalie;Mendis, Himasha;Dias, Daniel Anthony
通讯作者：
Dias, Daniel Anthony
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
50.3
作者：
Jones CL;Stevens BM;D'Alessandro A;Reisz JA;Culp-Hill R;Nemkov T;Pei S;Khan N;Adane B;Ye H;Krug A;Reinhold D;Smith C;DeGregori J;Pollyea DA;Jordan CT
通讯作者：
Jordan CT
DOI：
10.1096/fj.201800547r
发表时间：
2018-06-07
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Khurshed M;Aarnoudse N;Hulsbos R;Hira VVV;van Laarhoven HWM;Wilmink JW;Molenaar RJ;van Noorden CJF
通讯作者：
van Noorden CJF
影响因子：
8.8
作者：
Gelman SJ;Naser F;Mahieu NG;McKenzie LD;Dunn GP;Chheda MG;Patti GJ
通讯作者：
Patti GJ