Divergent medulloblastoma chromatin states disclose KDM2B as a selective dependency [CUT&Run]

Medulloblastoma (MB) is a biologically heterogeneous childhood cerebellar tumor harboring frequent chromatin-modifying gene alterations. How these alterations promote transcriptional programs governing malignancy remains poorly defined. To address this knowledge gap, we evaluated chromatin states across MB subgroups by multi-modal integration of histone modifications with mutational, DNA methylation, and transcriptomic profiles. A bivalent/poised enhancer (EnhBiv) state was specifically enriched at the promoters of neurodevelopmental genes in Groups 3 and 4-MB. Integrative bioinformatics coupled with chromatin occupancy studies identified aberrant KDM2B binding at EnhBiv-enriched promoters. CRISPR-mediated knockout or acute protein degradation of KDM2B selectively suppressed the growth of MB models in vitro and in vivo. Mechanistically, KDM2B promotes sequential recruitment of Polycomb repressive complexes (PRC1/PRC2) and EnhBiv chromatin, thereby repressing neuronal differentiation programs. Collectively, we provide foundational insights into an epigenetic basis of MB, nominating KDM2B as a selective dependency in high-risk subgroups that warrants consideration as a candidate therapeutic target.