Friend or foe-IDH1 mutations in glioma 10 years on

Abstract

The identification of recurrent point mutations in the isocitrate dehydrogenase 1 (IDH1) gene, albeit in only a small percentage of glioblastomas a decade ago, has transformed our understanding of glioma biology, genomics and metabolism. More than 1000 scientific papers have been published since, propelling bench-to-bedside investigations that have led to drug development and clinical trials. The rapid biomedical advancement has been driven primarily by the realization of a neomorphic activity of IDH1 mutation that produces high levels of (d)-2-hydroxyglutarate, a metabolite believed to promote glioma initiation and progression through epigenetic and metabolic reprogramming. Thus, novel inhibitors of mutant IDH1 have been developed for therapeutic targeting. However, numerous clinical and experimental findings are at odds with this simple concept. By taking into consideration a large body of findings in the literature, this article analyzes how different approaches have led to opposing conclusions and proffers a counterintuitive hypothesis that IDH1 mutation is intrinsically tumor suppressive in glioma but functionally undermined by the glutamate-rich cerebral environment, inactivation of tumor-suppressor genes and IDH1 copy-number alterations. This theory also provides an explanation for some of the most perplexing observations, including the scarcity of proper model systems and the prevalence of IDH1 mutation in glioma.

Figure 1.

Heterozygous IDH1^R132H induces epigenetic and metabolic reprogramming by inhibiting 2-oxoglutarate-dependent dioxygenases in glioma. (a) A diagram depicts the IDH1^R132H neomorphic activity in the cytosol that catalyzes D-2HG production through the hydroxylation of 2-oxoglutarate from IDH1-mediated oxidation of isocitrate. Consequently, D-2HG acts as an antagonist of 2-oxoglutarate primarily to inhibit histone demethylase KDM4C and 5-methylcytosine hydroxylase TET, resulting in histone methylation (H3K9me3) and CpG methylation (5mCpG). High levels of D-2HG induce HIF-1 signaling by inhibiting HIF prolyl 4-hydroxylase EGLN and subsequently induce L-2HG production. (b) Accumulation of succinate and fumarate in the mitochondria, resulting from mutations in the genes encoding succinate dehydrogenase (SDH) and fumarate hydratase (FH), respectively, inhibits HIF prolyl 4-hydroxylase EGLN, thereby stimulating HIF-1 signaling for tumorigenesis. Enhanced events are highlighted in solid color, whereas inhibited events are shaded gray.

Figure 2.

Mechanisms for undermining tumor-suppressive activity of heterozygous IDH1^R132H during glioma progression. (a) In the absence of extracellular glutamate, heterozygous IDH1^R132H, together with intact tumor-suppressor genes (e.g. TP53 and RB), obliterates oncogenic promotion of gliomagenesis. (b) Glutamate in the cerebral cortex negates IDH1^R132H suppression of gliomagenesis, thereby driving anchorage-independent growth and glioma progression, which is further exacerbated by the inactivation of tumor-suppressor genes and the selection against IDH1^R132H heterozygosity. The inhibited events are shaded gray.