Divergent medulloblastoma chromatin states disclose KDM2B as a selective dependency

Abstract Medulloblastoma 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 medulloblastoma 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 Group 3/4 medulloblastoma. 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 medulloblastoma 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 medulloblastoma, nominating KDM2B as a selective dependency in high-risk subgroups that warrants consideration as a candidate therapeutic target.

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Publication Details

Journal
Nature Genetics
Published
2026-09-24
DOI
https://doi.org/10.1038/s41588-026-02745-1
Primary Topic
Glioma Diagnosis and Treatment
Type
article
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article

Divergent medulloblastoma chromatin states disclose KDM2B as a selective dependency

Lena M. Kutscher, Colleen A. Reilly, Richa Bajpai, Jennifer L. Hadley et al.
Nature Genetics
Glioma Diagnosis and Treatment
article

Divergent medulloblastoma chromatin states disclose KDM2B as a selective dependency

Lena M. Kutscher, Colleen A. Reilly, Richa Bajpai, Jennifer L. Hadley, Emily Darrow, Mohamed Nadhir Djekidel, Rahul Kumar, Shondra M. Pruett‐Miller, Jamy C. Peng, Gang Wu, Serap Erkek, Brent A. Orr, Priya Mittal, Laura Sieber, David Filipovic, Stefan M. Pfister, Leena Paul, Ruijie Xu, Paul A. Northcott, Sebastian M. Waszak, Lukas Chávez, Melissa Batts, Natarajan V. Bhanu, Giles W Robinson, Marc Zapatka, Yurika Matsui, Beisi Xu, Ivo Buchhalter, Jan O. Korbel, Sara A. Lewis, Marcel Kool, Volker Hovestadt, David Jones, Benjamin Aaron Garcia, Xin Zhou, Yiran Li, Peter Lichter, Taha Soliman, Brian Gudenas, Kim Lowe, Marina Ryzhova, Kyle S. Smith, Qingsong Gao, Andrey Korshunov, Hong Lin, Ran Tao
article en

Abstract

Abstract Medulloblastoma 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 medulloblastoma 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 Group 3/4 medulloblastoma. 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 medulloblastoma 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 medulloblastoma, nominating KDM2B as a selective dependency in high-risk subgroups that warrants consideration as a candidate therapeutic target.

Nature Genetics
Broad Institute (US), St. Jude Children's Research Hospital (US), Children’s Institute (US), Izmir University (TR), Mayo Clinic (US), German Cancer Research Center (DE), Sanford Burnham Prebys Medical Discovery Institute (US), Washington University in St. Louis (US), Heidelberg University (DE), Discovery Institute (US), University Hospital Heidelberg (DE), WinnMed (US), University Medical Center Utrecht (NL), University of California San Diego (US), National Center for Tumor Diseases (DE), Hopp Children's Cancer Center Heidelberg (DE), Dana-Farber Cancer Institute (US), Burdenko Neurosurgery Institute (RU), Princess Máxima Center (NL), European Molecular Biology Laboratory (DE), Deutsches Konsortium für Translationale Krebsforschung (DE), Rady Children's Institute for Genomic Medicine (US)
Good health and well-being
Openalex Percentile: Top 12%
Glioma Diagnosis and Treatment
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