Genetic Dissection of the Biological and Molecular Role of IDH1 Mutations in Glioma

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2012

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Reitman, Zachary J.

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Abstract

Gliomas are tumors of the central nervous system for which improvements in treatment are critically needed. Mutations in IDH1 and IDH2, which encode the cytosolic and mitochondrial NADP+-dependent isocitrate dehydrogenases, respectively, are frequent in gliomas. Here, we summarize recent literature concerning gliomas, the normal cellular functions of IDH1/2, the epidemiology of IDH1/2 mutations, and the understanding of the function of IDH1/2 mutations in cancer. We then show in vitro using liquid chromatography-mass spectrometry that a function of many IDH1/2 mutations is to produce 2-hydroxyglutarate. Next, we use a mass spectrometry based platform to characterize metabolic changes in a glioma cell line expressing IDH1/2 mutants and show that the IDH mutants are associated with lowered N-acetylated amino acids both in this cell line model and in primary tumor tissue. Finally, we develop and characterize a Drosophila melanogaster (fruit fly) model of IDH1/2-mutated cancer by expressing the mutated Drosophila homolog of IDH1 in fly tissues using the UAS-Gal4 binary expression system. These results delineate downstream molecular players that likely play a role in IDH1/2-mutated cancer and provide a model organism for interrogation of genetic networks that interact with IDH1/2 mutation. These findings refine our understanding of glioma pathogenesis and may inform the design of new glioma therapies.

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Reitman, Zachary J. (2012). Genetic Dissection of the Biological and Molecular Role of IDH1 Mutations in Glioma. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/5418.

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