Mutations of isocitrate dehydrogenase 1 (IDH1) gene are most common in glioma, arguably preceding all known genetic alterations during tumor development. IDH1 mutations nearly invariably target the enzymatic active site Arg132, giving rise to the predominant IDH1^R132H. Cells harboring IDH1 ^R132H -heterozygous mutation produce 2-hydroxyglutarate (2-HG), which results in histone and DNA hypermethylation. Although exogenous IDH1 ^R132H transduction has been shown to promote anchorage-independent growth, the biological role of IDH1^R132H in glioma remains debatable. In this study, we demonstrate that heterozygous IDH1 ^R132H suppresses but hemizygous IDH1 ^R132H promotes anchorage-independent growth. Whereas genetic deletion of the wild-type allele in IDH1 ^R132H -heterozygous cells resulted in a pronounced increase in neurosphere genesis, restoration of IDH1 expression in IDH1 ^R132H -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 to IDH1 ^R132H -hemizygous neurosphere, IDH1 ^R132H -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 of IDH1 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.

异柠檬酸脱氢酶1（IDH1）基因的突变在神经胶质瘤中最常见，可以说是在肿瘤发展过程中所有已知的遗传改变之前。IDH1突变几乎总是靶向酶促活性位点Arg132，从而产生了主要的IDH1 ^R132H。细胞窝藏IDH1 ^R132H -heterozygous突变产生2-羟基戊二酸（2-HG），其结果在组蛋白和DNA甲基化。尽管已显示外源性IDH1 ^R132H转导可促进锚定非依赖性生长，但IDH1 ^R132H在神经胶质瘤中的生物学作用仍然值得商^bat。在这项研究中，我们证明了杂合IDH1 ^R132H 抑制但半合IDH1 ^R132H促进不依赖锚定的生长。IDH1 ^R132H-杂合子细胞中野生型等位基因的遗传缺失导致神经球的发生显着增加，而IDH1 ^R132H-杂合子细胞中IDH1表达的恢复却相反。相反，不依赖锚定的生长通过抑制基因表达和2-HG产生而拮抗突变IDH1功能。此外，我们发现与IDH1 ^R132H-嗜血神经球相反，IDH1 ^R132H -杂合细胞保持低水平的还原能力来抑制神经球的发生，但是可以通过添加还原剂来绕开。综上，这些结果强调了IDH1突变杂合性在神经胶质瘤生物学中的功能重要性，并表明突变IDH1的功能丧失是作为神经胶质瘤进展的逃逸机制，而氧化还原稳态是潜在的治疗靶点。