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Publications

Journal Article Ahead of print

PubMed: 42786297 DOI: 10.1038/s41588-026-02745-1

Divergent medulloblastoma chromatin states disclose KDM2B as a selective dependency.

Nat Genet

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

Affiliations

  • Center of Excellence in Neuro-Oncology Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Hopp Children´s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
  • Department of Pediatric Hematology and Oncology, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
  • Izmir Biomedicine and Genome Center, Inciralti, Izmir, Turkey.
  • Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
  • Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA.
  • Department of Cell & Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA.
  • Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
  • JRG Developmental Origins of Pediatric Cancers, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Division of Pediatric Glioma Research (B360), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany.
  • Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
  • University Medical Center Utrecht, Utrecht, the Netherlands.
  • Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Omics IT and Data Management Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Department of Neuropathology, Burdenko Neurosurgical Institute, Moscow, Russia.
  • Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
  • Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Department of Medicine, University of California San Diego, San Diego, CA, USA.
  • Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA, USA.
  • Rady Children's Institute for Genomic Medicine, Rady Children's Hospital and Healthcare Center, San Diego, CA, USA.
  • Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Bridging Research Division on Mechanisms of Genomic Variation and Data Science, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Center of Excellence in Neuro-Oncology Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.

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.

MeSH

Genes, Promoter Regions, Genetic, Neoplasms, Chromatin, Medulloblastoma, Dependency, Psychological