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

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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Publication Details

Journal
Neuro-Oncology
Published
2025-11-01
DOI
https://doi.org/10.1093/neuonc/noaf201.0022
Primary Topic
Glioma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
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article

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

Lena M. Kutscher, Colleen A. Reilly, Richa Bajpai, Kyle S. Smith et al.
Neuro-Oncology
Glioma Diagnosis and Treatment
article

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

Lena M. Kutscher, Colleen A. Reilly, Richa Bajpai, Kyle S. Smith, Jennifer L. Hadley, Emily Darrow, Qingsong Gao, Rahul Kumar, Shondra M. Pruett‐Miller, Jamy C. Peng, Taha Soliman, Gang Wu, Serap Erkek, Brent A. Orr, Priya Mittal, Stefan M. Pfister, Leena Paul, Ruijie Xu, Paul A. Northcott, Melissa Batts, Natarajan V. Bhanu, Giles W Robinson, Brian Gudenas, Yurika Matsui, Beisi Xu, Hong Lin, Jan O. Korbel, Nadhir Djekidel, Yiran Li, Benjamin Aaron Garcia, Xin Zhou, KF Lowe, Ran Tao
article en

Abstract

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.

Neuro-OncologyVol. 27(Supplement_5)
European Bioinformatics Institute (GB), St. Jude Children's Research Hospital (US), German Cancer Research Center (DE), Washington University in St. Louis (US), Heidelberg University (DE), European Molecular Biology Laboratory (ES), Hopp Children's Cancer Center Heidelberg (DE), European Molecular Biology Laboratory (DE), Deutsches Konsortium für Translationale Krebsforschung (DE)
Openalex Percentile: Top 51%
Glioma Diagnosis and Treatment
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