IDH1 R132H decreases proliferation of glioma cell lines in vitro and in vivo

Objective: A high percentage of grade II and III gliomas have mutations in the gene encoding isocitrate dehydrogenase (IDH1). This mutation is always a heterozygous point mutation that affects the amino acid arginine at position 132 and results in loss of its native enzymatic activity and gain of alternative enzymatic activity (producing D-2-hydroxyglutarate). The objective of this study was to investigate the cellular effects of R132H mutations in IDH1. Methods: Functional consequences of IDH1R132Hmutations were examined among others using fluorescence-activated cell sorting, kinome and expression arrays, biochemical assays, and intracranial injections on 3 different (glioma) cell lines with stable overexpression of IDH1R132H. Results: IDH1R132Hoverexpression in established glioma cell lines in vitro resulted in a marked decrease in proliferation, decreased Akt phosphorylation, altered morphology, and a more contact-dependent cell migration. The reduced proliferation is related to accumulation of D-2-hydroxyglutarate that is produced by IDH1R132H. Mice injected with IDH1R132HU87 cells have prolonged survival compared to mice injected with IDH1wtor green fluorescent protein-expressing U87 cells. Interpretation: Our results demonstrate that IDH1R132Hdominantly reduces aggressiveness of established glioma cell lines in vitro and in vivo. In addition, the IDH1R132H-IDH1wtheterodimer has higher enzymatic activity than the IDH1R132H-IDH1R132Hhomodimer. Our observations in model systems of glioma might lead to a better understanding of the biology of IDH1 mutant gliomas, which are typically low grade and often slow growing. Copyright

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