| IDH2 is a mitochondrial NADP+-dependent isocitrate dehydrogenase that catalyzes the reversible conversion of isocitrate to α-ketoglutarate while generating NADPH required for oxidative stress control and mitochondrial redox balance. As a homodimeric enzyme of the IDH family, IDH2 supports tricarboxylic acid cycle activity, glutathione regeneration, and metabolic homeostasis in hematopoietic and other proliferating cells. Cancer-associated mutations such as R140Q and R172K alter the catalytic activity of IDH2 and confer a neomorphic function that converts α-ketoglutarate into the oncometabolite (R)-2-hydroxyglutarate (2-HG) through NADPH-dependent reduction. Accumulation of 2-HG inhibits α-ketoglutarate-dependent dioxygenases, including TET2 and Jumonji-domain histone demethylases, resulting in DNA and histone hypermethylation, impaired chromatin remodeling, and blockade of myeloid differentiation programs. Mutant IDH2-driven epigenetic reprogramming maintains leukemic stem cell properties and cooperates with signaling alterations such as FLT3 or NRAS mutations to sustain leukemogenesis in acute myeloid leukemia. R140Q mutation disrupts substrate coordination within the catalytic site, whereas R172K alters allosteric regulation and shifts substrate preference toward α-ketoglutarate reduction. Elevated 2-HG levels also modulate inflammatory and survival signaling pathways, including NF-κB within the bone marrow microenvironment. Wild-type IDH2 contributes to hematopoietic progenitor proliferation and granulocytic maturation, while its mitochondrial localization distinguishes its metabolic functions from cytosolic IDH1. IDH2 mutations are detected in a significant subset of acute myeloid leukemia cases and are therapeutically targeted by selective inhibitors which suppress 2-HG production and restore cellular differentiation programs. |
