Cited by 744Acute Myeloid Leukemia ResearchGlioma Diagnosis and TreatmentCancer, Hypoxia, and Metabolism

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Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations

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Gross, Stefan, Cairns, Rob A., Minden, Mark D., Driggers, Edward M., Bittinger, Mark A., Jang, Hyun Gyung, Sasaki, Masato, Jin, Shengfang, Schenkein, David P., Su, Shinsan M., Dang, Lenny, Fantin, Valeria R., Mak, Tak W.·2010·Journal of Experimental Medicine

DOI 10.1084/jem.20092506PMC PMC2822606

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Abstract

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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Figure 1. IDH1/2 mutant AML cells and sera have increased levels of 2-HG. (A) Extracts from IDH1/2 WT (n = 10) and IDH1/2 mutant (n = 16) patient leukemia cells obtained at presentation and relapse, and IDH1 R132 mutant leukemia cells grown in culture for 14 d (n = 14) were analyzed by LC-MS to measure levels of 2-HG. (B) 2-HG was measured in sera of patients with IDH1 WT or IDH1 R132 mutant leukemia. In A and B, each point represents an individual patient sample. Diamonds represent WT, circles represent IDH1 mutants, and triangles represent IDH2 mutants. Horizontal bars indicate the mean. * indicates a statistically significant difference relative to WT patient cells (P < 0.05).CC BY-NC-SA · PubMed Central

Figure 2. IDH1/2 mutant AML cells do not display altered levels of central carbon metabolites. Extracts from leukemia cells of AML patients carrying an IDH1/2 mutant allele (mutant; n = 16) or WT (n = 10) obtained at initial presentation and relapse were assayed by LC-MS for levels of α-KG, succinate, malate, and fumarate. Each point represents an individual patient sample. Open circles represent WT, closed circles represent IDH1 mutants, and triangles represent IDH2 mutants. Horizontal bars represent the mean. There were no statistically significant differences between the WT and IDH1/2 mutant AML samples.CC BY-NC-SA · PubMed Central

Figure 3. Recombinant IDH1 R132C and IDH2 R172K produce 2-HG. (A) LC-MS analysis of in vitro reactions using recombinant IDH1 R132C and IDH2 R172K confirms that 2-HG and not isocitrate is the end product of the mutant enzyme reactions. Reactions were performed in triplicate in each of two independent experiments; typical chromatograms are presented. (B) The WT IDH1 enzyme catalyzes the oxidative decarboxylation of isocitrate to α-KG, with the concomitant reduction of NADP to NADPH. The IDH1 R132C and IDH2 R172K mutants reduce α-KG to 2-HG while oxidizing NADPH to NADP. These are referred to in the text as the “forward” and “partial reverse” reactions, respectively.CC BY-NC-SA · PubMed Central

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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: Cairns, Rob A.
Minden, Mark D.
Jang, Hyun Gyung
Sasaki, Masato
Dang, Lenny
Fantin, Valeria R.
Mak, Tak W.
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
DOI: 10.1084/jem.20092506
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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Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations

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