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
  • 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. [email protected].
  • # 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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