Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia

• Published in: Nature communications Vol. 13; no. 1; p. 2614
• Main Authors: Bassal, Mahmoud A., Samaraweera, Saumya E., Lim, Kelly, Benard, Brooks A., Bailey, Sheree, Kaur, Satinder, Leo, Paul, Toubia, John, Thompson-Peach, Chloe, Nguyen, Tran, Maung, Kyaw Ze Ya, Casolari, Debora A., Iarossi, Diana G., Pagani, Ilaria S., Powell, Jason, Pitson, Stuart, Natera, Siria, Roessner, Ute, Lewis, Ian D., Brown, Anna L., Tenen, Daniel G., Robinson, Nirmal, Ross, David M., Majeti, Ravindra, Gonda, Thomas J., Thomas, Daniel, D’Andrea, Richard J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.05.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/31; 13/44; 45/23; 631/67/2327; 631/67/68; 692/4028/67/1990/283/1897; Acute myeloid leukemia; Adult; Citric acid; Electron transport chain; Epistasis; Genomics; Germ-Line Mutation; Humanities and Social Sciences; Humans; Inhibitors; Isocitrate dehydrogenase; Isocitrate Dehydrogenase - genetics; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Metabolism; Mitochondria; Mitochondrial DNA; multidisciplinary; Mutants; Mutation; NADH-ubiquinone oxidoreductase; Science; Science (multidisciplinary); Sensitivity; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-30223-9

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.