IDH2 Gene

The IDH2 gene (isocitrate dehydrogenase (NADP(+)) 2 gene) is a protein coding gene located on chromosome 15q26.1. The protein encoded by the IDH2 gene is NADP(+)-dependent isocitrate dehydrogenase, an enzyme located in mitochondria. The enzyme plays a role in intermediary metabolism and energy production. Alternative splicing leads to several transcript variants.

Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two different subclasses, one of which uses NAD(+) as an electron acceptor and the other NADP(+). Five isocitrate dehydrogenases are known: three NAD(+)-dependent isocitrate dehydrogenases localized in the mitochondrial matrix and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isoenzyme is a homodimer.

IDH2 mutations have been observed in a number of tumor types, including sarcomas, hematologic malignancies, colon carcinoma, and gliomas/glioblastomas (Yan H et al. 2009).

The most common mutations involve R132(IDH1) and R172 (IDH2), which affect the active site of the enzyme and result in altered enzyme activity. Although IDH2 (R172) mutations are associated with a worse overall prognosis in AML patients, their value as a prognostic marker in MDS is still unclear.

Furthermore, IDH2 (R140) has been associated with improved overall survival in AML. IDH2 mutations are associated with "lower grade gliomas" (Gusyatiner O et al. 2018).

1. Bergaggio E et al (2019) IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies. Blood 133:156-167.
2. Gusyatiner O et al (2018) Glioma epigenetics: From subclassification to novel treatment options. Semin Cancer Biol 51:50-58.
3. Yan H et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765-773.