Molecular Pathways: IDH2 Mutations-Co-opting Cellular Metabolism for Malignant Transformation.
Review
Overview
abstract
Mutations in mitochondrial IDH2, one of the three isoforms of IDH, were discovered in patients with gliomas in 2009 and subsequently described in acute myelogenous leukemia (AML), angioimmunoblastic T-cell lymphoma, chondrosarcoma, and intrahepatic chloangiocarcinoma. The effects of mutations in IDH2 on cellular metabolism, the epigenetic state of mutated cells, and cellular differentiation have been elucidated in vitro and in vivo. Mutations in IDH2 lead to an enzymatic gain of function that catalyzes the conversion of alpha-ketoglutarate to beta-hydroxyglutarate (2-HG). Supranormal levels of 2-HG lead to hypermethylation of epigenetic targets and a subsequent block in cellular differentiation. AG-221, a small-molecule inhibitor of mutant IDH2, is being explored in a phase I clinical trial for the treatment of AML, other myeloid malignancies, solid tumors, and gliomas.
