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

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. Casolari, Diana G. Iarossi, Ilaria S. Pagani, Jason Powell, Stuart Pitson, Siria Natera, Ute Roessner, Ian D. Lewis, Anna L. Brown, Daniel G. Tenen, Nirmal Robinson, David M. Ross, Ravindra Majeti, Thomas J. Gonda, Daniel Thomas and Richard J. D’Andrea ()
Additional contact information
Mahmoud A. Bassal: Harvard Medical School
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
Daniel G. Tenen: Harvard Medical School
Nirmal Robinson: University of South Australia and SA Pathology
David M. Ross: University of South Australia and SA Pathology
Ravindra Majeti: Stanford University
Thomas J. Gonda: University of South Australia
Daniel Thomas: University of Adelaide
Richard J. D’Andrea: University of South Australia and SA Pathology

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30223-9

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