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.

神经胶质瘤和白血病仍然对治疗具有高度的抵抗力，因此强调了对新的和改进的治疗策略的需求。在星形细胞瘤和继发性胶质母细胞瘤以及急性髓细胞性白血病中经常遇到编码涉及三羧酸（TCA）循环的酶的基因突变，例如异柠檬酸脱氢酶1和2（IDH1 / 2）。然而，这些突变促进肿瘤发生的确切分子机制仍有待充分表征。已显示IDH1 / 2的功能获得性突变可刺激致癌代谢物R -2-羟基戊二酸（R-2HG），可抑制α-酮戊二酸（αKG）依赖性酶。我们审查IDH1 / 2突变的致癌功能阐明和相关的oncometabolite R -2HG的最新进展，其将改变的癌细胞代谢与表观遗传学，RNA甲基化，细胞信号转导，低氧反应和DNA修复联系起来。