( R )-2-Hydroxyglutarate Is Sufficient to Promote Leukemogenesis and Its Effects Are Reversible
Open accessAbstract
Focusing on the Right Metabolite: A variety of human cancers, including acute leukemias and brain tumors, have mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1, IDH2), which cause overproduction of a metabolite called 2-hydroxyglutarate (2HG). Losman et al. (p. 1621 , published online 7 February) show that the R - but not the S -enantiomer of 2HG can transform cells and that R -2HG mediates transformation at least in part through effects on protein modifying EglN prolyl hydroxylases. Importantly, the transforming activity of R -2HG was reversible, suggesting that therapeutic strategies focusing on inhibition of R -2HG production or inhibition of EglN prolyl hydroxylases merit further investigation.
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A high level of R-2-HG is sufficient to cause leukemia to arise from hematopoietic cells by maintaining their dedifferentiation and proliferation activities.
“A high level of R-2-HG is sufficient to cause leukemia to arise from hematopoietic cells by maintaining their dedifferentiation and proliferation activities116.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [116]
R-2HG is sufficient to promote cytokine independence and block differentiation of hematopoietic cells in vitro, and these effects are rapidly reversed upon R-2HG withdrawal.
“Interestingly, R-2HG is sufficient to promote cytokine independence and block differentiation of hematopoietic cells in vitro and these effects are fairly rapidly reversed upon R-2HG withdrawal (Losman et al., 2013; K. Yen, personal communication).”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Losman et al., 2013
Ectopic expression of mutant IDH allele or treatment with exogenous D-2-HG induces DNA and histone hypermethylation and blocks cellular differentiation.
“In various cellular settings, ectopic expression of a mutant IDH allele or treatment with exogenous D-2-HG is sufficient to induce DNA and histone hypermethylation and block cellular differentiation (Losman et al., 2013; Lu et al., 2012).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Losman et al., 2013
Cellular reprogramming elicited by D-2-HG may play a prominent role in the pathogenesis of IDH-mutant tumours.
“all suggesting that cellular reprogramming elicited by D-2-HG may play a prominent role in the pathogenesis of IDH-mutant tumours135-137.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [135]
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- Authors
- Losman, J.-A., Looper, R. E., Koivunen, P., Lee, S., Schneider, R. K., McMahon, C., Cowley, G. S., Root, D. E., Ebert, B. L., & Kaelin, W. G.
- Affiliations
- Brigham and Women's Hospital (US)
- University of Utah (US)
- University of Oulu (FI)
- Dana-Farber Cancer Institute (US)
- Broad Institute (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Kaelin, William G.
- ORCID
- Venue
- Science
- Published
- 2013-03-29
- Volume
- 339
- Issue
- 6127
- Pages
- 1621-1625
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3836459
- OpenAlex
- W2012588998
- Cited by
- 703
- References
- 32
- Citations by year
- 2026: 17 · 2025: 23 · 2024: 43 · 2023: 31 · 2022: 50 · 2021: 70 · 2020: 49 · 2019: 43 · 2018: 68 · 2017: 60 · 2016: 67 · 2015: 56 · 2014: 63 · 2013: 62
- FWCI
- 59.57
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R01CA068490)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK049216)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- (R)-2-hydroxyglutarate, leukemogenesis, IDH1 R132H mutation, IDH2 mutation, isocitrate dehydrogenase, enantiomers, TET2, hematopoietic differentiation, reversible transformation, cancer cell models
- MeSH terms
- Cell Transformation, Neoplastic, Glutarates, Hematopoiesis, Humans, Isocitrate Dehydrogenase, Leukemia, Models, Biological, Procollagen-Proline Dioxygenase, Cell Line, Tumor
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