SC-33POLYCOMB GROUP PROTEIN Bmi1 CONTROLS NEURAL STEM AND PROGENITOR CELL MAINTENANCE AND GLIOBLASTOMA TUMOUR DEVELOPMENT
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abstract
Bmi1, a polycomb group protein is required for self-renewal of neural stem and progenitor cells (NSPCs). Elevated Bmi1 expression is observed in most brain tumours, including glioblastoma (GBM). GBM, one of the most aggressive and heterogeneous tumours is known to possess a subpopulation of brain tumour initiating cells (BTICs) that have acquired stem cell properties and are exclusively capable of driving tumour formation in a human-mouse xenograft model. These observations raise the question of whether over-expressing Bmi1 is sufficient to promote self-renewal or tumorigenesis by NSPCs and whether loss of Bmi1 in GBM BTICs affects the progression of brain tumours. Using lentiviral constructs, we studied the gain of Bmi1 in human NSPCs and observed increased self-renewal and proliferative capacity of these cells. Subsequently, OEBmi1 NSPCs were injected in NOD-SCID mouse brains to assess their tumorigenic ability. Furthermore, knockdown of Bmi1 was performed in human GBM BTICs, which resulted in inhibition of clonogenic potential in vitro as well as decreased tumour cell mass in vivo. Lastly, to determine the comprehensive Bmi1 transcriptional network in human NSPCs and GBM BTICs, we applied ChIP-seq strategy to discover if Bmi1 binds to the promoter region of genes critical for neural lineage commitment and if these genes are involved in brain tumour formation. Together with RNA-seq data from human NSPCs and GBM BTICs sorted for stem cell marker CD133, this data will generate a comprehensive genome-wide Bmi1 binding profile and identify critical downstream Bmi1 targets & signaling pathways important for brain tumour maintenance.
