Abstract 33: Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

Abstract

Abstract Mutations in the enzyme isocitrate dehydrogenase 1 (IDH1) are a common feature of most gliomas and secondary glioblastomas, as well as approx 10% acute myeloid leukemias. This event results in loss of the enzyme's ability to catalyze conversion of isocitrate to α -ketoglutarate. However, these mutations are all heterozygous and occur at a single amino acid residue of the IDH1 active site consistent with an enzymatic gain of function rather than a simple loss of function. To test this hypothesis we characterized mutant IDH1 (IDH1m) biochemically. We have shown that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2-HG). Patients with an inherited, neurometabolic disorders called 2-hydroxyglutaric aciduria exhibit an accumulation of 2-HG in their CNS, and an increased risk of developing malignant brain tumors. Similarly, in human malignant gliomas harboring IDH1 mutations, we find elevated levels of 2-HG. Altogether our data demonstrate that the IDH1 mutations result in production of 2-HG, and suggest that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 33.