Abstract
Heterozygous mutations in the gene encoding isocitrate dehydrogenase (IDH) occur in gliomas, but their mechanistic role in tumor development is unknown. Tumor-derived IDH mutations impair the enzyme's affinity for its substrate and dominantly inhibit wild-type IDH1 activity through the formation of catalytically inactive heterodimers. Forced expression of mutant IDH1 in cultured cells reduces formation of the enzyme product, ?-ketoglutarate (?-KG), and increases the levels of hypoxia-inducible factor subunit 1 (HIF-1?, a transcription factor that facilitates tumor growth when oxygen is low and whose stability is regulated by ?-KG. HIF-1? levels were higher in human gliomas harboring an IDH1 mutation than in tumors without a mutation, thus, IDH1/2 contributes to tumor progression in part through induction of the HIF-1 pathway. Numerous independent research groups had demonstrated the role of IDH mutations as a prognostic marker, especially for those patients with low grade gliomas and secondary glioblastomas with oligodendroglial pattern. This knowledge indicates great opportunities to improve diagnostic and therapeutic strategies for gliomas, which are not currently targeted at the specific molecular alterations. This paper presents a detailed review of the role of the IDH gene mutations in progression and manteinance of gliomas, and explores some therapeutic options directed against this environment.
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