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  3. 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

  • Nat Commun. 2022 May 12;13(1):2614. doi: 10.1038/s41467-022-30223-9.
Mahmoud A Bassal  # 1 2,  Saumya E Samaraweera  # 3,  Kelly Lim 4,  Brooks A Benard 5,  Sheree Bailey 6,  Satinder Kaur 4,  Paul Leo 7,  John Toubia 3,  Chloe Thompson-Peach 4,  Tran Nguyen 3,  Kyaw Ze Ya Maung 3,  Debora A Casolari 3,  Diana G Iarossi 3,  Ilaria S Pagani 8,  Jason Powell 3,  Stuart Pitson 3,  Siria Natera 9,  Ute Roessner 9,  Ian D Lewis 10,  Anna L Brown 3 6 11,  Daniel G Tenen 1 2,  Nirmal Robinson 3,  David M Ross 3 4 8 12,  Ravindra Majeti 5,  Thomas J Gonda 6 13,  Daniel Thomas 4 5 8,  Richard J D'Andrea 14
Affiliations

Affiliations

  • 1 Harvard Stem Cell Institute, Harvard Medical School, Boston, USA.
  • 2 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • 3 Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia.
  • 4 Discipline of Medicine, University of Adelaide, Adelaide, Australia.
  • 5 Hematology Division, Department of Medicine, Stanford Cancer Institute, Institute for Stem Cell and Regenerative Medicine, Stanford University, Stanford, USA.
  • 6 Clinical and Health Sciences, University of South Australia, Adelaide, Australia.
  • 7 Diamantina Institute, Translational Research Institute, Brisbane, Australia.
  • 8 Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, Australia.
  • 9 Metabolomics Australia, The University of Melbourne, Melbourne, Australia.
  • 10 Adelaide Oncology & Haematology, Adelaide, Australia.
  • 11 Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.
  • 12 Department of Clinical Haematology, Royal Adelaide Hospital, Adelaide, Australia.
  • 13 School of Pharmacy, University of Queensland, Brisbane, Australia.
  • 14 Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia. Richard.DAndrea@unisa.edu.au.
  • # Contributed equally.
PMID: 35551192 DOI: 10.1038/s41467-022-30223-9
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.

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