Epigenetic-Mediated Dysfunction of the BMP Pathway Inhibits Differentiation of Human Glioblastoma Initiating Cells

Despite similarities between tumor initiating cells with stem-like properties (TICs) and normal neural stem cells, we hypothesized that there may be differences in their differentiation potentials. We now demonstrate that both bone morphogenetic protein (BMP)-mediated and ciliary neurotrophic factor (CNTF)-mediated Jak/STAT-dependent astroglial differentiation is impaired due to EZH2-dependent epigenetic silencing of BMP receptor 1B (BMPR1B) in a subset of glioblastoma TICs. Forced expression of BMPR1B either by transgene expression or demethylation of the promoter restores their differentiation capabilities and induces loss of their tumorigenicity. We propose that deregulation of the BMP developmental pathway in a subset of glioblastoma TICs contributes to their tumorigenicity both by desensitizing TICs to normal differentiation cues, and by converting otherwise cytostatic signals to pro-proliferative signals. Keywords: Genomic alterations DNA extracted from four glioma cell lines were hybridized to 50K mapping arrays (Xba only) to detect and summarize chromosomal aberrations in those samples.