Journal article
Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia
MA Bassal, SE Samaraweera, K Lim, BA Bernard, S Bailey, S Kaur, P Leo, J Toubia, C Thompson-Peach, T Nguyen, KZY Maung, DA Casolari, DG Iarossi, IS Pagani, J Powell, S Pitson, S Natera, U Roessner, ID Lewis, AL Brown Show all
Nature Communications | NATURE PORTFOLIO | Published : 2022
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-mut..
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Awarded by Snowdome Foundation
Funding Acknowledgements
M.A.B. Ph.D. scholarship funding was courtesy of the USAPA. M.A.B. and D.G.T. were supported by Singapore Ministry of Health's National Medical Research Council (Singapore Translational Research (STaR)) Investigator Award STaR 18nov-0002, the Singapore Ministry of Education under its Research Centres of Excellence initiative, and National Institutes of Health, National Cancer Institute (NIH/NCI) Grant R35CA197697 and NIH/NHLBI P01HL131477-01A1. B.A.B. was supported by the Blavatnik Family Foundation and NIH training grant 5T32CA9302-40. This work was also supported by the NIH/NCI Grant 1R01CA251331 (R.M.), the Ludwig Institute for Cancer Stem Cell Research and Medicine (R.M.) and the Leukaemia and Lymphoma Society Translational Research Programme grant 6619-21 (R.M. and D.T.), co-funded by Snowdome Foundation and the Leukaemia Foundation of Australia. R.M. is a Leukaemia & Lymphoma Society Scholar. D.T. is supported by a Commonwealth Serum Laboratories Centenary Fellowship, Australian Medical Research Future Fund Stem Cells Mission (2008972), National Health and Medical Research Council Australia Ideas Grants 1182564 & 1184485, Beat Cancer Infrastructure Grant (IF1320) and The Hospital Research Foundation (C-PJ-173-Exper-2019). This project was funded by the Royal Adelaide Hospital Contributing Haematologists' Committee (I.D.L., R.J.D., and S.E.S.), the National Health and Medical Research Council Australia (GNT1047129, R.J.D., T.J.G., A.L.B., I.D.L.) and through the financial and other support of Cancer Council SA's Beat Cancer Project (2002137, R.J.D., D.M.R., and T.J.G.) on behalf of its donors and the State Government of South Australia through the Department of Health. We thank all patients who gave samples for this study, and the South Australian Cancer Research Biobank (SACRB) for their assistance with sample collection and storage. Metabolomics analyses was conducted by Metabolomics Australia at The University of Melbourne, a NCRIS initiative under Bioplatforms Australia Pty Ltd.