Modeling the origins of glioma with human embryonic stem cells

When gliomas are found in younger patients, they are often less aggressive (“low-grade” gliomas) but inevitably transform into more aggressive tumors. The early steps in gliomagenesis, i.e. the process whereby a normal brain cell turns into a glioma cell, are not well understood. We recently developed the first human model of low-grade astrocytoma using neural stem cells derived from human embryonic stem cells. We engineered these neural stem cells to express genetic changes found in low-grade astrocytoma, including the neomorphic IDH1 mutation and loss of P53 and ATRX. We found that these genetic alterations arrested the ability of neural stem cells to differentiate, which we hypothesize is the dominant cellular mechanism in oncogenic transformation. This block of differentiation is underlain by changes in chromatin conformation, which lead to reorganization of transcription factor networks regulating multipotency and differentiation. We are employing genetic, biochemical and pharmacologic approaches to dissect the epigenetic mechanisms responsible for glioma initiation and validate novel molecular dependencies of glioma cells.