Isocitrate dehydrogenase 2 (NADP+), mitochondrial (Mutant R172) (IDH2)

Mutant IDH2 R172 refers to a specific oncogenic variant of the mitochondrial enzyme isocitrate dehydrogenase 2 (NADP+), mitochondrial (Stein et al., 2017). In its wild-type state, IDH2 catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) as part of the tricarboxylic acid (TCA) cycle (Stein et al., 2017). Mutations at the arginine 172 (R172) residue, such as R172K or R172S, confer a neomorphic gain-of-function that converts α-KG into the oncometabolite D-2-hydroxyglutarate (2-HG) (OncoKB; Stein et al., 2017). The accumulation of 2-HG competitively inhibits α-KG-dependent dioxygenases, including TET family DNA demethylases and Jumonji-C domain-containing histone demethylases (Nassereddine et al., 2017). This leads to global DNA and histone hypermethylation, which blocks the differentiation of hematopoietic and other progenitor cells (AACR Journals). Such epigenetic dysregulation drives the development of malignancies such as acute myeloid leukemia (AML), angioimmunoblastic T-cell lymphoma (AITL), and certain solid tumors (Frontiers in Oncology; OncoKB). Therapeutic targeting of mutant IDH2 R172 with selective inhibitors like enasidenib aims to reduce 2-HG levels, thereby restoring normal epigenetic control and promoting the differentiation of malignant cells into mature, functional cells (Stein et al., 2017; Nassereddine et al., 2017). Clinical monitoring of treatment efficacy often involves measuring 2-HG levels and assessing the mutation status of the IDH2 gene (OncoKB). Safety concerns associated with these therapies include differentiation syndrome and indirect hyperbilirubinemia (De Botton et al., 2022).

Other names

IDH2 R172KIDH2 R172SIDH2 R172GIDH2 R172MIDH2 R172WIDH2 R172TmIDH2 R172Isocitrate dehydrogenase 2 R172

Selective allosteric inhibition of the mutant IDH2 enzyme to reduce 2-hydroxyglutarate (2-HG) levels and restore cellular differentiation (Stein et al., 2017; Nassereddine et al., 2017).