Biochemical Characterization and Genetic Modeling of Glioma-Associated Mutations in Isocitrate Dehydrogenases.
Gliomas are the most common tumors of the central nervous system. Our lab recently identified mutations in <italic>IDH1</italic> and <italic>IDH2</italic> as occurring frequently in progressive gliomas. We applied a series of biochemical and genetic approaches to explore the roles of the mutations in tumors and generate models for study.
<italic>IDH1/2</italic> mutations have the potential to impact a number of metabolic pathways. IDH1/2 convert isocitrate to α-ketoglutarate while simultaneously converting NADP+ to NADPH. To assess changes in metabolism, we completed metabolic profiling and complementary studies in cell lines with and without mutant <italic>IDH1</italic> or mutant <italic>IDH2</italic>. We identified a decrease in hypoxia signaling and a decrease in global 5-hydroxymethylcytosine in cell lines with mutant <italic>IDH1/2</italic> .
Having observed mutations in <italic>IDH1/2</italic> in a large fraction of progressive gliomas, we asked if the mutations were either 1) advantageous for growth in brain parenchyma, or 2) advantageous in a particular cell-of-origin. Sequencing of a series of metastases to the brain from non-central nervous system tumors identified no mutations in <italic>IDH1/2</italic>, lending less credence to the first hypothesis. To elucidate whether mutations in <italic>IDH1/2</italic> can initiate glioma progression and explore the potential cell-of-origin for progressive gliomas, we generated mice in which we induced expression of mutant <italic>IDH2</italic> in different populations of cells in the brain, either alone or in combination with <italic>TP53</italic> deletion, another frequently altered gene in progressive gliomas. Mice with broad expression of mutant <italic>IDH2</italic> developed hydrocephalus and encephalomalacia early in life, but did not develop tumors. Therefore, we restricted expression, and two brain tumors were identified in mice with both <italic>IDH2</italic> mutation and <italic>TP53</italic> deletion. While this suggests that both mutations might be required for the development of tumors, this is too small a number to draw significant conclusions. Further research with an expanded cohort of mice, utilization of additional drivers of expression, and further characterization of identified tumors will help in elucidating the role of mutant <italic>IDH2</italic> and the cell-of-origin for progressive gliomas.
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