ArticleNature communications2022
Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 21 citations in OpenAlex.
- Mitochondrial transfer technologies with molecular insights into clinical applications.Stem cells (Dayton, Ohio) · 2026Review
- Deleterious mitochondrial heteroplasmy drives high-risk clonal hematopoiesis and hematological malignancy.medRxiv : the preprint server for health sciences · 2026Article
- Metformin induces ferroptosis associated with lipidomic remodeling in AML.Blood advances · 2026Article
- Targeting mitochondrial homeostasis as a cancer treatment strategy: current status and future prospects.Molecular cancer · 2026Review
- IDH1 mutation creates a dependency on fatty acid metabolism that underlies sensitivity to cuproptosis in acute myeloid leukemia cells.International journal of medical sciences · 2026Article
- Disrupting tRNA modifications to target mitochondrial vulnerabilities in drug-resistant leukemia cells.Blood · 2025Article
- Integrating multi-omics approaches in acute myeloid leukemia (AML): Advancements and clinical implications.Clinical and experimental medicine · 2025Review
- High mtDNA content identifies oxidative phosphorylation-driven acute myeloid leukemias and represents a therapeutic vulnerability.Signal transduction and targeted therapy · 2025Article
- Mitochondrial heteroplasmy improves risk prediction for myeloid neoplasms.Nature communications · 2024Article
- Article
- Application of omics in the diagnosis, prognosis, and treatment of acute myeloid leukemia.Biomarker research · 2024Review
- IDH1-mutant preleukemic hematopoietic stem cells can be eliminated by inhibition of oxidative phosphorylation.Blood cancer discovery · 2024Article
- Article
- The curious case of IDH mutant acute myeloid leukaemia: biochemistry and therapeutic approaches.Biochemical Society transactions · 2023Review
- The Interplay between Dysregulated Metabolism and Epigenetics in Cancer.Biomolecules · 2023Review
- Dysregulated Lipid Synthesis by Oncogenic IDH1 Mutation Is a Targetable Synthetic Lethal Vulnerability.Cancer discovery · 2023Article
- The Mystery of EVP4593: Perspectives of the Quinazoline-Derived Compound in the Treatment of Huntington's Disease and Other Human Pathologies.International journal of molecular sciences · 2022Review
- Emerging Roles of NDUFS8 Located in Mitochondrial Complex I in Different Diseases.Molecules (Basel, Switzerland) · 2022Review
Corrections and comments
- Erratum issued
Authors and funding
27 authors at 9 institutions in 3 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.