Isocitrate dehydrogenase 1 R132H mutant neoantigen (IDH1 R132H neoantigen)

The isocitrate dehydrogenase 1 R132H mutant is a neomorphic variant of the cytoplasmic enzyme isocitrate dehydrogenase 1 (IDH1), where arginine-132 is replaced by histidine. This mutation is one of the most prevalent driver events in lower-grade gliomas and is also found in other cancers such as acute myeloid leukemia and chondrosarcoma. Unlike wild-type IDH1, which catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate with NADP⁺ as a cofactor (producing NADPH), the R132H mutant possesses new ("neomorphic") enzymatic activity: it reduces α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate (D-2HG). D-2HG accumulates to high levels in tumor cells with this mutation, competitively inhibiting α-ketoglutarate–dependent dioxygenases; this leads to global DNA and histone hypermethylation, altered cell differentiation, and a proneoplastic cellular state. The R132H mutant is highly tumor-specific and immunogenic, making it a neoantigen—and thus an attractive target for immunotherapies and small-molecule inhibitors. Two small-molecule oral inhibitors, ivosidenib and olutasidenib, have been approved for cancers harboring mutant IDH1, acting via allosteric inhibition of the mutant protein. Detection of D-2HG and molecular identification of the R132H mutation serve as key biomarkers for patient diagnosis and selection for targeted therapy.

Other names

IDH1 R132H mutantMutant isocitrate dehydrogenase 1 R132HD-2-hydroxyglutarate-producing IDH1IDH1 R132HmIDH1 R132H

Allosteric inhibition of mutant IDH1 enzymatic activity, leading to reduced D-2-hydroxyglutarate production Selective binding to mutant versus wild-type IDH1