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

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 8_Supplement; p. 33
• Main Authors: Fantin, Valeria R., Dang, Lenny, White, David W., Gross, Stefan, Bittinger, Mark A., Driggers, Edward M., Jang, Hyun Gyung, Jin, Shengfang, Keenan, Marie C., Marks, Kevin M., Yen, Katharine E., Ward, Patrick S., Prins, Robert M., Liau, Linda M., Bennett, Bryson D., Rabinowitz, Joshua D., Cantley, Lewis C., Thompson, Craig B., Heiden, Matthew Vander, Su, Shinsan M.
• Format: Journal Article
• Language: English
• Published: 15.04.2010
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM10-33

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.