ACTIVE CHROMATIN IN H3K27M DIPG REVEALS DISTINCT EPIGENETIC SUBTYPES AND SUBTYPE-SPECIFIC MECHANISMS OF PATHOGENESIS

DIPG is the leading cause of pediatric brain tumor-related death and remains without effective clinical treatment. Through numerous genomic studies, the H3K27M mutation has emerged as the molecular hallmark of DIPG. While this mutation causes global chromatin remodeling and a broadly oncogenic transcriptional signature, the core molecular pathways driving DIPG pathobiology remain to be defined. In this study, we characterize the active chromatin epigenomic landscape of DIPG in a large cohort of primary tumor samples and identify novel epigenetic subgroups within histone-mutant DIPG. We uncover distinct signaling pathways controlling oncogenic state for each subgroup, elucidating novel mechanisms mediating proliferation and treatment resistance. Utilizing a human iPSC developmental model introducing the histone mutation at progressive stages of neural precursor differentiation, we will describe the developmental cell state most closely resembling DIPG tumors from each genomic subgroup and identify the specific molecular pathways by which the H3K27M mutant drives transformation. Taken together, this study identifies functional molecular heterogeneity between primary DIPG tumors and characterizes novel targets for potential therapeutic development.