MDB-09. IMPACT OF PRDM6 ON CHROMATIN ACCESSIBILITY, GENE EXPRESSION, AND MEDULLOBLASTOMA FORMATION

Abstract Group 4 medulloblastoma (MB) is the most common subgroup and shows high incidence of metastasis late-onset relapse cases. These tumors lack a unifying oncogenic driver treatment targets, despite extensive genomic characterization. MBs are characterized by recurrent genetic alterations in chromatin modifiers amplification stemness genes. A substantial fraction enhancer hijacking through tandem duplication SNCAIP, resulting expression PRDM6, putative transcriptional repressor histone methyltransferase. Some PRDM6-overexpressing cases show additional mutations regulators MYCN expression. We set out to elucidate impact potential sustained PRDM6 early neural stem cell populations patient-derived cells. find that human iPSC-derived neuroepithelial cells (NESCs) results tumor growth mice at low penetrance. Moreover, we MYCN-overexpressing NESCs does not further alter aggressiveness or survival vivo. Notably, overexpression 3 MYC-amplified D283-Med line causes significantly increased shorter mice. At cellular level, localizes nucleus, suggesting role gene regulation. Consistent with this notion, ATAC-seq RNA-seq analysis PRDM6-NESCs PRDM6-D283-Med reveals major changes accessibility expression, specifically upregulation integrin family members focal adhesion extracellular matrix receptor interaction pathways. conclude promotes may play maintenance interactions microenvironment.