The Emerging Role of D-2-Hydroxyglutarate as an Oncometabolite in Hematolymphoid and Central Nervous System Neoplasms

• Main Authors: Dinesh eRakheja, L Jeffrey Medeiros, Scott eBevan, Weina eChen
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2013-07-01
• Series: Frontiers in Oncology
• Subjects: Glioma; Acute Myeloid Leukemia; IDH mutation; NPM1 mutation; D-2-Hydroxyglutarate
• Online Access: http://journal.frontiersin.org/Journal/10.3389/fonc.2013.00169/full

Approximately 20% of unselected cases and 30% cytogenetically diploid cases of acute myeloid leukemia (AML) and 80% of grade II-III gliomas and secondary glioblastomas carry mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. IDH1/2 mutations prevent oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) and modulate the function of IDH (neomorphic activity) thereby facilitating reduction of α-KG to D-2-hydroxyglutarate (D-2HG), a putative oncometabolite. D-2-hydroxyglutarate is thought to act as a competitive inhibitor of α-KG-dependent dioxygenases that include prolyl hydroxylases and chromatin-modifying enzymes. The end result is a global increase of cellular DNA hypermethylation and alterations of the cellular epigenetic state, which has been proposed to play a role in the development of a variety of tumors. In this review, we provide an update on potential molecular mechanisms linking IDH1/2 mutations and the resulting oncometabolite, D-2HG, with malignant transformation. In addition, in patients with AML and glioma we focus on the associations between IDH1/2 mutations and clinical, morphologic, cytogenetic, and molecular characteristics.