Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia
In: pii: 10.1038/s41467-022-30223-9; Bassal, M. A., Samaraweera, 2022
Online
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Zugriff:
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.
Titel: |
Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia
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Autor/in / Beteiligte Person: | Bassal, MA ; Samaraweera, SE ; Lim, K ; Bernard, BA ; Bailey, S ; Kaur, S ; Leo, P ; Toubia, J ; Thompson-Peach, C ; Nguyen, T ; Maung, KZY ; Casolari, DA ; Iarossi, DG ; Pagani, IS ; Powell, J ; Pitson, S ; Natera, S ; Roessner, U ; Lewis, ID ; Brown, AL ; Tenen, DG ; Robinson, N ; Ross, DM ; Majeti, R ; Gonda, TJ ; Thomas, D ; D'Andrea, RJ |
Link: | |
Zeitschrift: | pii: 10.1038/s41467-022-30223-9; Bassal, M. A., Samaraweera, 2022 |
Veröffentlichung: | NATURE PORTFOLIO, 2022 |
Medientyp: | academicJournal |
ISSN: | 2041-1723 (print) |
DOI: | 10.1038/s41467-022-30223-9. |
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