Mutations in genes encoding isocitrate dehydrogenase (IDH) enzymes occur first in the cascade of genetic changes that lead to the formation of glioma, the most common type of malignant brain tumor, in about 35% of adolescent patients that develop this form of cancer. However, the mechanisms of tumor initiation by IDH oncogenes are not well understood. To address this issue, we created a genetic mouse model of this disease which revealed that IDH mutations alter the function and fate of neural stem and progenitor cells prior to tumor development. Further, we discovered that a gene that plays a key role in dictating neural stem and progenitor cell fate is silenced by IDH mutations, implicating...

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Mutations in genes encoding isocitrate dehydrogenase (IDH) enzymes occur first in the cascade of genetic changes that lead to the formation of glioma, the most common type of malignant brain tumor, in about 35% of adolescent patients that develop this form of cancer. However, the mechanisms of tumor initiation by IDH oncogenes are not well understood. To address this issue, we created a genetic mouse model of this disease which revealed that IDH mutations alter the function and fate of neural stem and progenitor cells prior to tumor development. Further, we discovered that a gene that plays a key role in dictating neural stem and progenitor cell fate is silenced by IDH mutations, implicating this change as a potential driving force in brain tumor development. We propose to test whether these alterations play a causal role in brain tumor initiation and define the underlying cause of these alterations at the molecular level. In addition to revealing the basic biology of glioma development, our findings may inform new molecular tests to predict or monitor antitumor efficacy of mutant IDH inhibitor drugs in adolescent glioma patients. These drugs have shown promising activity in late-stage clinical trials, but identifying patients who are likely to respond to this class of drugs could be aided by the creation of companion molecular tests.

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