| Description |
Heterozygous missense point mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are the most common genetic alteration in the primary brain tumor, gliomas. This mutation results in a neomorphic function that catalyzes the reductive conversion of 2- oxoglutarate to 2-hydroxyglutarate (2-HG), leading to a downstream global DNA and histone hypermethylation. Beyond this, however, the role of IDH mutations in glioma progression remains controversial. Despite its significant survival benefit, there are several cornerstone findings in the field that demonstrate its tumorigenic properties. However, more studies come to light, demonstrating the tumor suppressive molecular signature of IDH mutated versus wild-type gliomas. Likewise, there is also increasing evidence that IDH1 mutant functional heterozygosity and 2-HG production is often compromised at recurrence, further justifying the need to reexamine the role of IDH mutation in gliomas. To this end, we developed in vitro and in vivo models of the most common variant in gliomas: IDH1R132H mutated tumors. We showed that IDH1R132H mutant heterozygous, but not 2-HG deficient hemizygous IDH1R132H, is antagonistic to anchorage-independent growth and suppressive of tumor growth. We also showed that IDH1R132H is intrinsically tumor suppressive, but the glutamate-rich cerebral microenvironment can bypass this suppression. We used the in vitro model of spheroid IDH heterozygous cells and demonstrated its reduced oncogenic expression profile relative to hemizygous cells. We also identified a potential mechanistic justification for tumor suppression-downregulation iv of neural stem cell marker nestin. Finally, we also uncovered the potential for loss of heterozygosity and environmental glutamate as modes of escape for IDH mutant gliomas. Our study has redefined the role of IDH mutations by emphasizing heterozygosity and its concomitant 2-HG production, and not just the mutant itself, as tumor suppressive. Overall, this paradigm shift may improve how IDH mutations are studied, with greater implications on how gliomas are targeted in the clinic. |
