Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations
- PMID: 20142433
- PMCID: PMC2822606
- DOI: 10.1084/jem.20092506
Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations
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 alpha-ketoglutarate (alpha-KG) to 2-HG. The IDH1 R132C mutation commonly found in AML reduces the affinity for isocitrate, and increases the affinity for NADPH and alpha-KG. This prevents the oxidative decarboxylation of isocitrate to alpha-KG, and facilitates the conversion of alpha-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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Comment in
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Cancers converge at 2-HG.J Exp Med. 2010 Feb 15;207(2):265. doi: 10.1084/jem.2072iti5. Epub 2010 Feb 8. J Exp Med. 2010. PMID: 20142426 Free PMC article. No abstract available.
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Metabolism and the leukemic stem cell.J Exp Med. 2010 Apr 12;207(4):677-80. doi: 10.1084/jem.20100523. Epub 2010 Apr 5. J Exp Med. 2010. PMID: 20368582 Free PMC article.
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References
-
- Bleeker F.E., Lamba S., Leenstra S., Troost D., Hulsebos T., Vandertop W.P., Frattini M., Molinari F., Knowles M., Cerrato A., et al. 2009. IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum. Mutat. 30:7–11 10.1002/humu.20937 - DOI - PubMed
-
- Ducray F., Marie Y., Sanson M. 2009. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360:2248. - PubMed
-
- Hartmann C., Meyer J., Balss J., Capper D., Mueller W., Christians A., Felsberg J., Wolter M., Mawrin C., Wick W., et al. 2009. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol. 118:469–474 10.1007/s00401-009-0561-9 - DOI - PubMed
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