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Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia. Nature communications Bassal, M. A., Samaraweera, S. E., Lim, K., Bernard, B. A., Bailey, S., Kaur, S., Leo, P., Toubia, J., Thompson-Peach, C., Nguyen, T., Maung, K. Z., Casolari, D. A., Iarossi, D. G., Pagani, I. S., Powell, J., Pitson, S., Natera, S., Roessner, U., Lewis, I. D., Brown, A. L., Tenen, D. G., Robinson, N., Ross, D. M., Majeti, R., Gonda, T. J., Thomas, D., D'Andrea, R. J. 2022; 13 (1): 2614

Abstract

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.

View details for DOI 10.1038/s41467-022-30223-9

View details for PubMedID 35551192