EPCO-28. DOT1L AND PRC2 REGULATE A SHARED EPIGENETIC MECHANISM IN GLIOBLASTOMA AND MIXED LINEAGE LEUKEMIA

Abstract Glioblastoma (GBM) is the most aggressive adult brain tumor, with a median survival of 15 months despite current treatments. We recently established that epigenetic regulator Disruptor Telomeric Silencing-1-Like (DOT1L) was essential for growth tumor stem cells (BTSCs), which are thought to underlie GBM initiation and treatment resistance. Given previously recognized importance DOT1L histone methylation regulation similarly rare childhood cancer, Mixed Lineage Leukemia (MLL), we interrogated common mechanisms in both BTSCs MLL cells, overlap due role DOT1L. To gain more detailed perspective mark BTSCs, performed chemogenomic screen using inhibitor, EPZ-5676. Results from this revealed genes transcriptional complexes required therapeutic response inhibition BTSCs. Gene targeting approaches assays further identified Polycomb Repressive Complex 2 (PRC2) as determining factor following inhibition. Furthermore, analysis chromatin accessibility changes regulated by PRC2 shared unique characteristics MLL. The extent these underpin pathogenic process distinct diseases being investigated assessing divergence responses emerge phenomenon. findings study will provide insight into tumorigenesis cancers affecting blood.