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

Author

Listed:
  • Mahmoud A. Bassal

    (Harvard Medical School
    National University of Singapore)

  • Saumya E. Samaraweera

    (University of South Australia and SA Pathology)

  • Kelly Lim

    (University of Adelaide)

  • Brooks A. Benard

    (Stanford University)

  • Sheree Bailey

    (University of South Australia)

  • Satinder Kaur

    (University of Adelaide)

  • Paul Leo

    (Translational Research Institute)

  • John Toubia

    (University of South Australia and SA Pathology)

  • Chloe Thompson-Peach

    (University of Adelaide)

  • Tran Nguyen

    (University of South Australia and SA Pathology)

  • Kyaw Ze Ya Maung

    (University of South Australia and SA Pathology)

  • Debora A. Casolari

    (University of South Australia and SA Pathology)

  • Diana G. Iarossi

    (University of South Australia and SA Pathology)

  • Ilaria S. Pagani

    (South Australian Health and Medical Research Institute)

  • Jason Powell

    (University of South Australia and SA Pathology)

  • Stuart Pitson

    (University of South Australia and SA Pathology)

  • Siria Natera

    (The University of Melbourne)

  • Ute Roessner

    (The University of Melbourne)

  • Ian D. Lewis

    (Adelaide Oncology & Haematology)

  • Anna L. Brown

    (University of South Australia and SA Pathology
    University of South Australia
    SA Pathology)

  • Daniel G. Tenen

    (Harvard Medical School
    National University of Singapore)

  • Nirmal Robinson

    (University of South Australia and SA Pathology)

  • David M. Ross

    (University of South Australia and SA Pathology
    University of Adelaide
    South Australian Health and Medical Research Institute
    Royal Adelaide Hospital)

  • Ravindra Majeti

    (Stanford University)

  • Thomas J. Gonda

    (University of South Australia
    University of Queensland)

  • Daniel Thomas

    (University of Adelaide
    Stanford University
    South Australian Health and Medical Research Institute)

  • Richard J. D’Andrea

    (University of South Australia and SA Pathology)

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.

Suggested Citation

  • Mahmoud A. Bassal & Saumya E. Samaraweera & Kelly Lim & Brooks A. Benard & Sheree Bailey & Satinder Kaur & Paul Leo & John Toubia & Chloe Thompson-Peach & Tran Nguyen & Kyaw Ze Ya Maung & Debora A. Ca, 2022. "Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30223-9
    DOI: 10.1038/s41467-022-30223-9
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