Dissecting the Molecular Cascade Linking IDH1 Mutations with Gliomagenesis
IDH1 mutations are the signature genetic feature of lower grade gliomas and secondary glioblastomas. They are thought to initiate gliomagenesis by causing accumulation of the oncometabolite (R)-2-hydroxyglutarate in neural progenitor cells. (R)-2-hydroxyglutarate, in turn, controls the activity of dioxygenase enzymes which regulate chromatin structure, hypoxia signaling, and other key aspects of neural cell biology. Collectively, these effects promote brain tumor initiation. Although this framework represents a significant advance in our understanding of the oncogenicity of IDH1 mutations, detailed characterization of the molecular cascades that link (R)-2-hydroxyglutarate accumulation with gliomagenesis has not been fully completed.
We are currently undertaking complementary top-down and bottom-up approaches to dissect specific oncogenic mechanisms engaged by IDH1 mutations. To systematically identify critical proximal effectors of (R)-2-hydroxyglutarate in glioma, we are performing CRISPR/Cas9 screens to uncover dioxygenases that control malignant transformation in cellular contexts that closely recapitulate glioma genetics. We are also using a novel genetically-engineered mouse model of glioma created in our laboratory to characterize the dynamics of the distal effects of mutant IDH1 on the epigenome and the transcriptome. Taken together, findings from these studies are expected to provide a comprehensive understanding of how (R)-2-hydroxyglutarate induces glial cell transformation in vivo. These findings may reveal metabolic mechanisms of transformation with relevance beyond the setting of IDH1 mutant glioma. Furthermore, our findings may reveal unappreciated therapeutic opportunities to impede brain tumor progression.