Oncogenic Activities of IDH1/2 Mutations: From Epigenetics to Cellular Signaling

Gliomas and leukemias remain highly refractory to treatment, thus highlighting the need for new and improved therapeutic strategies. Mutations in genes encoding enzymes involved in the tricarboxylic acid (TCA) cycle, such as the isocitrate dehydrogenases 1 and 2 (IDH1/2), are frequently encountered in astrocytomas and secondary glioblastomas, as well as in acute myeloid leukemias; however, the precise molecular mechanisms by which these mutations promote tumorigenesis remain to be fully characterized. Gain-of-function mutations in IDH1/2 have been shown to stimulate production of the oncogenic metabolite R-2-hydroxyglutarate (R-2HG), which inhibits α-ketoglutarate (αKG)-dependent enzymes. We review recent advances on the elucidation of oncogenic functions of IDH1/2 mutations, and of the associated oncometabolite R-2HG, which link altered metabolism of cancer cells to epigenetics, RNA methylation, cellular signaling, hypoxic response, and DNA repair.