MB-20: WDR5 ORCHESTRATES CANCER CELL SELF RENEWAL IN Myc DRIVEN MEDULLOBLASTOMA

MYC oncogene driven medulloblastoma (MB) has a poor overall outcome and there is a need for more effective therapies. We hypothesized that epigenetic mechanisms may mediate MYC-driven medulloblastoma. To address this, we performed a functional epigenome wide RNAi screen targeting 406 epigenetic molecules associated with chromatin remodeling and histone modification in Myc MB cells. Unbiased analysis identified several key regulators of long-term viability in these Myc amplified MB cells. Remarkably we identified multiple proteins that are part of the COMPASS like macromolecular complex as critical mediators of MB cell viability. These include ASH2L, MLL2 (KMT2D), WDR5, DPY30 and HFC1. This complex is critical for methylation of histone 3 lysine 4 (H3K4me3) and mediating transcriptional activation. We established that WDR5 is important for MYC driven medulloblastoma cell survival. Knock down of WDR5 attenuates clonogenic growth of tumor cells, suppresses stem cell associated gene expression programs and prevents formation of new neurospheres suggesting an inhibition of self-renewal of the medulloblastoma cells. Co-immunoprecipitation studies revealed an interaction between cMYC and WDR5. Confocal microscopy using high cMYC medulloblastoma cells also demonstrated that WDR5 co-localizes with cMYC in nucleus. C-MYC overexpressing neural stem cells differentiate down a neuronal lineage upon WDR5 knockdown. We are now performing more detailed studies on the activity of WDR5 in vitro and in vivo in MYC driven medulloblastoma. Further characterization of WDR5 will provide deeper insight into understanding of group3 medulloblastoma and its therapeutic intervention.