Functional requirement of a wild-type allele for mutant IDH1 to suppress anchorage-independent growth through redox homeostasis

In this study, we demonstrate that heterozygousIDH1R132H suppresses but hemizygousIDH1R132H promotes anchorage-independent growth. Whereas genetic deletion of the wild-type allele inIDH1R132H-heterozygous cells resulted in a pronounced increase in neurosphere genesis, restoration ofIDH1 expression inIDH1R132H-hemizygous cells led to the contrary. Conversely, anchorage-independent growth was antagonistic to the mutant IDH1 function by inhibiting gene expression and 2-HG production. Furthermore, we identified that in contrast toIDH1R132H-hemizygous neurosphere,IDH1R132H-heterozygous cells maintained a low level of reducing power to suppress neurosphere genesis, which could be bypassed, however, by the addition of reducing agent. Taken together, these results underscore the functional importance ofIDH1 mutation heterozygosity in glioma biology and indicate functional loss of mutant IDH1 as an escape mechanism underlying glioma progression and the pathway of redox homeostasis as potential therapeutic targets.
Source: Acta Neuropathologica - Category: Neurology Source Type: research