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Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations
Open accessAbstract
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), are present in most gliomas and secondary glioblastomas, but are rare in other neoplasms. IDH1/2 mutations are heterozygous, and affect a single arginine residue. Recently, IDH1 mutations were identified in 8% of acute myelogenous leukemia (AML) patients. A glioma study revealed that IDH1 mutations cause a gain-of-function, resulting in the production and accumulation of 2-hydroxyglutarate (2-HG). Genotyping of 145 AML biopsies identified 11 IDH1 R132 mutant samples. Liquid chromatography-mass spectrometry metabolite screening revealed increased 2-HG levels in IDH1 R132 mutant cells and sera, and uncovered two IDH2 R172K mutations. IDH1/2 mutations were associated with normal karyotypes. Recombinant IDH1 R132C and IDH2 R172K proteins catalyze the novel nicotinamide adenine dinucleotide phosphate (NADPH)–dependent reduction of α-ketoglutarate (α-KG) to 2-HG. The IDH1 R132C mutation commonly found in AML reduces the affinity for isocitrate, and increases the affinity for NADPH and α-KG. This prevents the oxidative decarboxylation of isocitrate to α-KG, and facilitates the conversion of α-KG to 2-HG. IDH1/2 mutations confer an enzymatic gain of function that dramatically increases 2-HG in AML. This provides an explanation for the heterozygous acquisition of these mutations during tumorigenesis. 2-HG is a tractable metabolic biomarker of mutant IDH1/2 enzyme activity.
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“The high concentrations of R-2HG (more than 10 mM) that have been observed in malignant brain tumours and leukaemias (Dang et al, 2009;Gross et al, 2010;Ward et al, 2010), might be sufficient to inhibit even the less-susceptible 2OG oxygenases.”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Gross et al, 2010
In the citing paper
“However, they also cause a gain of function comprising catalysis of 2OG to the R-enantiomer of 2-hydroxyglutarate (R-2HG; Dang et al, 2009;Gross et al, 2010;Ward et al, 2010).”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Gross et al, 2010
In the citing paper
“Tumor-associated IDH mutations unmask a latent ability of these enzymes to produce the R enantiomer of 2-hydroxyglutarate, which accumulates to low millimolar levels in IDH mutant tumors (Dang et al., 2009; Gross et al., 2010; Ward et al., 2010).”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Gross et al., 2010
In the citing paper
“AML samples with low to undetectable 2HG were subsequently sequenced and determined to be IDH1 and IDH2 wild-type”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Gross et al., 2010
In the citing paper
“several samples with elevated 2HG were found to have neomorphic mutations at either IDH1 R132 or IDH2 R172 (Gross et al., 2010)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Gross et al., 2010
In the citing paper
“Enzymatic assays and measurement of 2HG levels in primary AML samples confirmed that these IDH2 R172 mutations result in 2HG elevation (Gross et al., 2010; Ward et al., 2010).”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Gross et al., 2010
In the citing paper
“serum 2HG levels have successfully correlated with IDH1 R132 mutations in AML”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Gross et al., 2010
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Metadata
- Authors
- Gross, S., Cairns, R. A., Minden, M. D., Driggers, E. M., Bittinger, M. A., Jang, H. G., Sasaki, M., Jin, S., Schenkein, D. P., Su, S. M., Dang, L., Fantin, V. R., & Mak, T. W.
- Affiliations
- Agios Pharmaceuticals Incorporated, Cambridge, MA 02139 1
- University Health Network (CA)
- Agios Pharmaceuticals (United States) (US)
- Corresponding author
- Fantin, Valeria R.
- Mak, Tak W.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2010-02-08
- Volume
- 207
- Issue
- 2
- Pages
- 339-344
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2822606
- OpenAlex
- W2159731673
- Cited by
- 736
- References
- 23
- Citations by year
- 2026: 10 · 2025: 19 · 2024: 34 · 2023: 35 · 2022: 29 · 2021: 55 · 2020: 40 · 2019: 36 · 2018: 45 · 2017: 51 · 2016: 61 · 2015: 44 · 2014: 49 · 2013: 61 · 2012: 61
- FWCI
- 45.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Leukemia and Lymphoma Society
- Agios Pharmaceuticals
- Terry Fox Foundation
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- 2-hydroxyglutarate, IDH mutation, acute myeloid leukemia, alpha-ketoglutarate, NADPH-dependent reduction, gain-of-function mutations, cancer metabolism, metabolic biomarkers
- MeSH terms
- Catalysis, Glutarates, Humans, Isocitrate Dehydrogenase, Ketoglutaric Acids, Mutation, NADP, Recombinant Proteins, Leukemia, Myeloid, Acute
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