Mutations in the Isocitrate Dehydrogenase Genes IDH1 and IDH2 in Tumors

Heterozygous hotspot mutations in isocitrate dehydrogenases (IDH) IDH1 or IDH2 are frequently observed in specific types of cartilaginous tumors, gliomas, and leukemias. Mutant IDH enzyme loses its normal activity to convert isocitrate into alpha-ketoglutarate (alpha KG) and instead acquires the ability to reduce alpha KG to D-2-hydroxyglutarate. Through direct competition with alpha KG, accumulation of the oncometabolite D-2-hydroxyglutarate in IDH mutated tumors results in inhibition of alpha KG-dependent dioxygenases involved in DNA and histone demethylation. Apart from epigenetic alterations, perturbations in the tricarboxylic acid cycle (depletion of intermediates) and activation of the intricately linked hypoxia signaling pathway are apparent in IDH mutated cells. As molecular details are being unraveled, the emerging concept is that IDH mutations result in tumor formation by epigenetic alterations that affect gene expression and result in inhibition of cellular differentiation. Activation of hypoxic stress signaling reprograms cellular energy metabolism and promotes anabolic processes and angiogenesis, thus, providing an advantage to promote neoplastic growth.