SC-19METABOLIC ALTERATIONS IN EARLY GLIOMAGENESIS

Gliomas are primary brain tumors with an incidence of over 20,000 new cases in the US annually, a poor prognosis and limited therapeutic options. Despite chemoradiotherapy and surgery, low-grade gliomas (LGGs) transform into high-grade gliomas, leading to neurological deterioration and death. Mutations in genes encoding Isocitrate Dehydrogenase (IDH) isoforms are found in up to 80% of LGGs. Among the three IDH genes, R132H-IDH1 represents the most prevalent mutation in LGGs. The mutation is a gain-of-function change at the catalytic site. Although IDH1 normally functions to convert isocitrate to α-ketoglutarate, the mutation leads to the production of the (R)-2-hydroxyglutarate (2HG) oncometabolite, causing characteristic DNA and histone methylation changes that are thought to contribute to tumorigenesis. To test the hypothesis that mutant IDH1 is a driver of gliomagenesis, we propose a novel approach in which we use human embryonic stem cells (hESCs) to model the tumorigenesis process: we inducibly overexpress the R132H-IDH1 protein in human neural stem cells, neuroblasts, oligodendrocyte progenitors and astrocytes that are derived from hESCs. Using lentiviral constructs and BAC-engineered hESC lines, this approach allows us to investigate the effects of 2HG on differentiation, self-renewal and transformative potential systematically along the human neuroglial axis both in vitro and in vivo. Using hESCs to understand IDH1-mediated oncogenesis is a novel strategy based on modeling a single oncogenic change in a human genetic background, potentially overcoming limitations found in current mouse models and further shedding light on early human gliomagenesis.