ArticleBlood cancer discovery2024
IDH1-mutant preleukemic hematopoietic stem cells can be eliminated by inhibition of oxidative phosphorylation.
Article in Blood cancer discovery, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed, 18 citations in OpenAlex.
- Circulating tumor DNA-based detection of molecular residual disease in isocitrate dehydrogenase-mutant cholangiocarcinoma for biomarker-guided therapy.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Dynamics of IDH1/2 mutated clones in acute myeloid leukemia challenge their use as universal MRD markers.Blood cancer journal · 2026Article
- IDH1- and IDH2-mutated myeloid neoplasms: mutational pattern, clonal hierarchy, and the role in AML transformation.Blood advances · 2026Article
- Novel and emerging therapeutic strategies for clonal hematopoiesis.Haematologica · 2026Review
- Metformin induces ferroptosis associated with lipidomic remodeling in AML.Blood advances · 2026Article
- 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
- Target practice: Opportunities for therapeutic intervention in CHIP and CCUS.Blood reviews · 2025Review
- Cancer stem cells: landscape, challenges and emerging therapeutic innovations.Signal transduction and targeted therapy · 2025Review
- High mtDNA content identifies oxidative phosphorylation-driven acute myeloid leukemias and represents a therapeutic vulnerability.Signal transduction and targeted therapy · 2025Article
- Dysregulation of Mitochondrial Function in Cancer Cells.International journal of molecular sciences · 2025Review
- Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis.Nature communications · 2025Article
- Review
- The LeukemicCancers · 2024Article
- Clinical Implications of Isocitrate Dehydrogenase Mutations and Targeted Treatment of Acute Myeloid Leukemia with Mutant Isocitrate Dehydrogenase Inhibitors-Recent Advances, Challenges and Future Prospects.International journal of molecular sciences · 2024Review
- Article
- Altered Oxidative Phosphorylation Confers Vulnerability on IDH1-Mutant Leukemia Cells: Is This Therapeutically Tractable?Blood cancer discovery · 2024Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 4 countries.
Funding
Abstract
Rare preleukemic hematopoietic stem cells (pHSC) harboring only the initiating mutations can be detected at the time of acute myeloid leukemia (AML) diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSC). We confirm that IDH1-driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in the complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wild-type HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent the development and relapse of leukemia. SIGNIFICANCE: A high burden of pHSCs is associated with worse overall survival in AML. Using single-cell sequencing, metabolic assessment, and gene-edited human models, we find human pHSCs with IDH1 mutations to be metabolically vulnerable and sensitive to eradication by complex I inhibition. See related commentary by Steensma.
Identifiers
What OpenQuestion holds
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.