IDH mutations in tumorigenesis and their potential role as novel therapeutic targets

Abstract

Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). Somatic mutations in genes encoding IDH1 and IDH2 were first identified in glioma and subsequently in acute myeloid leukemia and other solid tumors. These heterozygous point mutations occur at the arginine residue of the enzyme’s active site and cause both loss of normal enzyme function and gain of function, causing reduction of α-KG to D-2-hydroxyglutarate, which accumulates. D-2-hydroxyglutarate may act as an oncometabolite through the inhibition of various α-KG-dependent enzymes, stimulating angiogenesis, histone modifications and aberrant DNA methylation. Possibly, IDH mutations may also cause oncogenic effects through dysregulation of the tricarboxylic acid cycle, or by increasing susceptibility to oxidative stress. Clinically, IDH mutations may be useful diagnostic, prognostic and predictive biomarkers, and it is anticipated that a better understanding of the pathogenesis of IDH mutations will enable IDH-directed therapies to be developed in the future.