EPCO-22. DIVERGENT MEDULLOBLASTOMA CHROMATIN STATES DISCLOSE KDM2B AS A SELECTIVE DEPENDENCY

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Abstract Medulloblastoma (MB) is a highly malignant childhood cerebellar tumor comprising molecularly and clinically distinct subgroups. Groups 3 and 4-MB originate from overlapping progenitor pools of the developing rhombic lip when neuronal differentiation hierarchies are subverted through somatic alterations. Mutations suspected to deregulate the activity of chromatin-modifying genes are pervasive in Group 3/4-MB. However, molecular consequences of these alterations remain largely undefined. We characterized the chromatin landscape of fifty-two primary MBs using chromatin immunoprecipitation followed by sequencing (ChIP-seq) for six histone modifications and performed multi-modal integration with sample-matched somatic lesions, genome-wide DNA methylation, and transcriptomic profiles. Analysis of differential chromatin states across MB subgroups revealed significant enrichment of the bivalent enhancer state (EnhBiv; marked by coincident H3K4me1 and H3K27me3) in Group 3/4-MB overlapping neurodevelopmental genes. Integrative bioinformatics coupled with CUT&RUN analysis revealed significant enrichment of KDM2B, a histone lysine demethylase overexpressed in Group 4-MB, in gene promoters marked by the EnhBiv state. CRISPR gene targeting or targeted protein degradation of KDM2B selectively suppressed growth of Group 3 and Group 4-MB models in vitro and in vivo, which was dependent on KDM2B DNA-binding domain but not demethylase activity. Acute and chronic KDM2B degradation impaired EZH2 recruitment through direct physical interactions and indirect KDM2B-mediated PRC1 activity, reducing H3K27me3 deposition and chromatin bivalency, while profoundly derepressing PRC2 targets involved in neuronal differentiation. Our comprehensive characterization of the MB chromatin landscape in a large cohort of primary tumors provides unprecedented insights into the epigenetic basis of MB subgroups, implicating novel mechanisms of tumorigenesis, and disclosing a unique subgroup-specific dependency conferred by KDM2B-mediated Polycomb activity that warrants consideration as a novel therapeutic target.

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