During this past fiscal year, we continued our analysis of the microarray dataset that was initially reported in Lee et al., Cancer Cell (2006)9:391-403. This dataset contains gene expression data for freshly resected tumors and glioma stem cells (GSCs) derived from these tumors, both before and after differentiation. Analysis of the gene expression profiles revealed a number of specific intracellular signalling pathways that may be involved in the differentiation process of GSCs. In particular, we examined the role of a transcription factor (TF) that interacts with the CREB binding protein. This TF is overexpressed in GSCs compared to differentiated tumor cells and in clinical glioma specimens from patients with relatively shorter survival. The siRNA-mediated knockdown of the TF in GSCs inhibits proliferation, induces differentiation, decreases resistance to temozolomide and ionizing radiation, and prevents tumor formation. The TF acts by regulating the expression of proteins that in turn regulate Ezh2 activity. Our results reveal a central role for this TF in maintaining the stem cell state and tumorigenic capacity of GSCs and identify it as a potential therapeutic target.