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Medulloblastoma (MB) is one of the most common pediatric tumors in children. Among them, SHH subgroups of MB (MBSHH) is characterized by constitutive activation of SHH pathway. Somatic mutations in BRPF1, a chromatin modifier, is found in more than 5% of MBSHH and accounts for almost 20% of adult MBSHH but its potential role in MBSHH pathophysiology is still unknown. In this study, we first examined the function of Brpf1 on pro-tumorigenic features of MBSHH and evaluated molecular pathways regulated by Brpf1 using Brpf1floxed::Atoh1-Cre conditional knockout mice, in which Brpf1 is conditionally deleted in cerebellar granule neuron progenitors (GNPs). While RNA-seq analysis on GNPs from Brpf1 WT and KO mice showed significant differences in the pathways related with cell cycle and cell death, deletion of Brpf1 did not cause acceleration of tumorigenesis in the Ptch1 heterozygous tumor-prone. Background: Co-immunoprecipitation followed by mass spectrometry analysis identified interaction partners of BRPF1 including MOZ, MORF and ING5, known partners of BRPF1. Gene ontology analysis also depicted pathways important for cell cycle progression, cell death and response to DNA damage. Consistent with these observations, TP53 was identified as a novel co-factor of BRPF1. Of note, some of MBSHH-relevant BRPF1 mutations prevented interaction with TP53. According to the previous finding that cytosolic TP53 is required for apoptotic cell death, GNPs expressing the BRPF1-R600X mutant gene exhibited the resistance to irradiation-induced cell death. In conclusion, our data revealed that BRPF1 mutants found in MBSHH could prevent the complex formation with TP53, leading to enhanced resistance to cell apoptosis.

MBRS-51. MUTATIONS IN BRPF1 FOUND IN SHH MEDULLOBLASTOMA PREVENT INTERACTION WITH TP53 AND LEADS TO RADIORESISTANCE IN VITRO