| Abstract: |
IDH1 and IDH2 are homodimeric enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (α-KG) as part of the TCA cycle. Mutations in the genes encoding IDH1 and IDH2 have recently been found in glioma, acute myeloid leukemia (AML), chondrosarcoma, and intrahepatic cholangiocarcinoma. The mutant protein loses its normal enzymatic activity and gains a new ability to produce the ‘oncometabolite’ 2-hydroxyglutarate (R-2-HG). R-2-HG inhibits enzymes that play crucial roles in gene regulation and tissue homeostasis. Expression of mutant IDH impairs cellular differentiation in various cell lineages and promotes tumor development in cooperation with other cancer genes. First-generation inhibitors of mutant IDH have entered clinical trials and have shown encouraging results in patients with IDH-mutant AML. This chapter summarizes recent progress in our understanding of the role of mutant IDH in tumorigenesis. © Springer International Publishing AG 2017. |
