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.

• Authors: Stefan Gross, Rob A Cairns, Mark D Minden, Edward M Driggers, Mark A Bittinger, Hyun Gyung Jang, Masato Sasaki, Shengfang Jin, David P Schenkein, Shinsan M Su, Lenny Dang, Valeria R Fantin, Tak W Mak
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 207 Issue 2 Pg. 339-44 (Feb 15 2010) ISSN: 1540-9538 [Electronic] United States
• PMID: 20142433 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glutarates
• Ketoglutaric Acids
• Recombinant Proteins
• alpha-hydroxyglutarate
• NADP
• IDH2 protein, human
• Isocitrate Dehydrogenase
• IDH1 protein, human

Topics

• Catalysis
• Glutarates (blood)
• Humans
• Isocitrate Dehydrogenase (genetics, metabolism)
• Ketoglutaric Acids (metabolism)
• Leukemia, Myeloid, Acute (blood, enzymology, genetics)
• Mutation
• NADP (metabolism)
• Recombinant Proteins (metabolism)