Isocitrate dehydrogenase [NADP], mitochondrial (IDH2) R140Q (IDH2-R140Q)

Isocitrate dehydrogenase [NADP], mitochondrial (IDH2) R140Q is a gain-of-function mutant form of the IDH2 enzyme, which is normally responsible for converting isocitrate to alpha-ketoglutarate (α-KG) in the mitochondria [1, 6]. The R140Q mutation occurs at a critical arginine residue in the catalytic site, conferring a neomorphic enzymatic activity that converts α-KG into the oncometabolite (R)-2-hydroxyglutarate (2-HG) [1, 4]. The accumulation of 2-HG competitively inhibits α-KG-dependent dioxygenases, such as TET2 and histone demethylases, leading to widespread DNA and histone hypermethylation [5, 9]. This epigenetic dysregulation blocks the normal differentiation of hematopoietic cells, promoting the development of malignancies like acute myeloid leukemia (AML) [5, 10]. Targeted inhibitors such as enasidenib (AG-221) specifically bind to the mutant IDH2-R140Q protein to suppress 2-HG production, which restores cellular differentiation and has shown significant clinical efficacy in patients with relapsed or refractory AML [1, 8]. Monitoring 2-HG levels in the blood and bone marrow serves as a vital biomarker for tracking treatment response and target engagement [9].

Other names

IDH2 R140QmIDH2-R140QIsocitrate dehydrogenase 2 R140QIDH2 arginine 140 to glutamine mutant

Selective inhibition of mutant IDH2 enzyme activity to reduce production of the oncometabolite 2-hydroxyglutarate (2-HG) and restore normal cellular differentiation.