Abstract
Recurrent heterozygous mutation of isocitrate dehydrogenase 1 gene (IDH1), predominantly resulting in histidine substitution at arginine 132, was first identified in glioma. The biological significance of IDH1R132H, however, has been controversial, and its prevalent association with glioma remains enigmatic. Although recent studies indicate that IDH1R132H is nonessential to tumor growth or even anti-tumor growth, whether IDH1R132H initiates gliomagenesis remains obscure. In this study, we report that IDH1R132H is intrinsically tumor-suppressive but the activity can be attenuated by glutamate—the cerebral neurotransmitter. We observed that IDH1R132H was highly suppressive of subcutaneous tumor growth driven by platelet-derived growth factor B (PDGFB), but IDH1R132H tumor growth and glioma penetrance were virtually indistinguishable from those of IDH1-wildtype tumors in orthotopic models. In vitro, addition of glutamate compromised IDH1R132H inhibition of neurosphere genesis, indicating glutamate promotion of oncogenic dominance. Furthermore, we observed that IDH1R132H expression was markedly decreased in tumors but became more permissible upon the deletion of tumor-suppressor gene Cdkn2a. To provide direct evidence for the opposing effect of IDH1R132H on PDGFB-driven glioma development, we explored tandem expression of the two molecules from a single transcript to preclude selection against IDH1R132H expression. Our results demonstrate that when juxtaposed with oncogenic PDGFB, IDH1R132H overrides the oncogenic activity and obliterates neurosphere genesis and gliomagenesis even in the glutamate-rich microenvironment. We propose therefore that IDH1R132H is intrinsically suppressive of glioma initiation and growth but such tumor-suppressive activity is compromised by the glutamate-rich cerebral cortex, thereby offering a unifying hypothesis for the perplexing role of IDH1R132H in glioma initiation and growth.
Highlights
Heterozygous mutations in the isocitrate dehydrogenase 1 (IDH1) gene are found most frequently in glioma, predominantly resulting in the mutant enzyme IDH1R132H with histidine substitution at arginine 132 [1,2,3]
We reported recently that heterozygous IDH1R132H is functionally anti-oncogenic, as evidenced by the antagonism between IDH1R132H heterozygosity and anchorageindependent growth; whereas heterozygous IDH1R132H suppressed neurosphere genesis, the surviving neurosphere selected against the expression of either IDH1R132H or isocitrate dehydrogenase 1 gene (IDH1) transgene and reduced D2-HG levels [15]
We present evidence in this study that the outcome of IDH1R132H transduction in glioma initiation and growth is context dependent even though IDH1R132H is intrinsically tumor-suppressive
Summary
Heterozygous mutations in the isocitrate dehydrogenase 1 (IDH1) gene are found most frequently in glioma, predominantly resulting in the mutant enzyme IDH1R132H with histidine substitution at arginine 132 [1,2,3]. Our findings support the concept of IDH1R132H being anti-oncogenic and suggest the strong antagonism between tumor growth and heterozygous IDH1R132H expression in the experimental setting This interpretation is consistent with the requirement of a wild-type IDH1 allele for D2-HG production [16, 17] and the frequent loss of either wildtype or mutant IDH1 allele in patient-derived xenograft, ex vivo neurosphere culture, and glioma recurrence and progression [11, 16, 18, 19], even though the underlying mechanism of copy number alteration remains unclear
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