Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

2nd Department of Pediatrics Semmelweis University Budapest Hungary

Adaptive Oncology Ontario Institute for Cancer Research Toronto Ontario Canada

Alberta Children's Hospital Research Institute Calgary Alberta Canada

Assistance Publique Hôpitaux de Paris Hôpital Necker Enfants Malades Paris France

Brotman Baty Institute for Precision Medicine Seattle WA USA

Canada's Michael Smith Genome Sciences Centre BC Cancer Agency Vancouver British Columbia Canada

Cancer Research Program McGill University Health Centre Research Institute Montreal Quebec Canada

Cancer Research Program Research Institute of the McGill University Health Centre Montreal Quebec Canada

CancerCare Manitoba Research Institute Winnipeg Manitoba Canada

Cansearch Research Platform for Pediatric Oncology and Hematology Faculty of Medicine Department of Pediatrics Gynecology and Obstetrics University of Geneva Geneva Switzerland

CBIO Centre for Computational Biology PSL Research University MINES ParisTech Paris France

CEINGE Biotecnologie Avanzate Naples Italy

Center for Integrative Brain Research Seattle Children's Research Institute Seattle WA USA

Centre de Pathologie EST Groupement Hospitalier EST Université de Lyon Bron France

Charbonneau Cancer Institute University of Calgary Calgary Alberta Canada

Clinical Research Division Fred Hutchinson Cancer Research Center Seattle WA USA

Computational Biology Program Ontario Institute for Cancer Research Toronto Ontario Canada

Department of Anatomical and Cellular Pathology The Chinese University of Hong Kong Shatin Hong Kong

Department of Biochemistry and Medical Genetics University of Manitoba Winnipeg Manitoba Canada

Department of Biochemistry and Molecular Biology Cumming School of Medicine University of Calgary Calgary Alberta Canada

Department of Hematology and Medical Oncology Emory University School of Medicine and Winship Cancer Institute Atlanta GA USA

Department of Human Genetics McGill University Montreal Quebec Canada

Department of Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario Canada

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA

Department of Medical Biophysics University of Toronto Toronto Ontario Canada

Department of Medical Genetics University of British Columbia Vancouver British Columbia Canada

Department of Molecular Biology and Biochemistry Simon Fraser University Burnaby British Columbia Canada

Department of Molecular Genetics University of Toronto Toronto Ontario Canada

Department of Molecular Oncology BC Cancer Agency Vancouver British Columbia Canada

Department of Neurological Surgery University of California San Francisco San Francisco CA USA

Department of Neurological Surgery University of Pittsburgh School of Medicine Pittsburgh PA USA

Department of Neurological Surgery Vanderbilt Medical Center Nashville TN USA

Department of Neurology Erasmus University Medical Center Rotterdam Netherlands

Department of Neurology University of California San Francisco San Francisco CA USA

Department of Neurology Vanderbilt Medical Center Nashville TN USA

Department of Neurosurgery Chonnam National University Research Institute of Medical Sciences Chonnam National University Hwasun Hospital and Medical School Hwasun gun South Korea

Department of Neurosurgery Division of Pediatric Neurosurgery Seoul National University Children's Hospital Seoul South Korea

Department of Neurosurgery Duke University Durham NC USA

Department of Neurosurgery Hospital Infantil de Mexico Federico Gomez Mexico City Mexico

Department of Neurosurgery Kitasato University School of Medicine Sagamihara Japan

Department of Neurosurgery University of Alabama at Birmingham Birmingham AL USA

Department of Neurosurgery University of Ulsan Asan Medical Center Seoul South Korea

Department of Pathology and Laboratory Medicine Hamilton General Hospital Hamilton Ontario Canada

Department of Pathology and Laboratory Medicine University of British Columbia Vancouver British Columbia Canada

Department of Pathology and Molecular Medicine Division of Anatomical Pathology McMaster University Hamilton Ontario Canada

Department of Pathology Cedars Sinai Medical Center Los Angeles CA USA

Department of Pathology Duke University Durham NC USA

Department of Pathology Erasmus University Medical Center Rotterdam Netherlands

Department of Pathology St Jude Children's Research Hospital Memphis TN USA

Department of Pathology The Children's Memorial Health Institute Warsaw Poland

Department of Pathology University of California San Francisco San Francisco CA USA

Department of Pediatric Neurosurgery Santobono Pausilipon Children's Hospital Naples Italy

Department of Pediatric Oncology Hematology Immunology and Pulmonology University Hospital Heidelberg Heidelberg Germany

Department of Pediatric Oncology Masaryk University School of Medicine Brno Czech Republic

Department of Pediatrics and Child Health and Department of Biochemistry and Medical Genetics Rady Faculty of Health Sciences University of Manitoba Winnipeg Manitoba Canada

Department of Pediatrics Hematology and Oncology Case Western Reserve Cleveland OH USA

Department of Pediatrics University of California San Francisco San Francisco CA USA

Department of Pediatrics University of Colorado Denver Aurora CO USA

Department of Surgery and Anatomy Faculty of Medicine of Ribeirão Preto University of São Paulo São Paulo Brazil

Department of Surgery Division of Thoracic and Upper Gastrointestinal Surgery Faculty of Medicine McGill University Montreal Quebec Canada

Department of Surgery The Chinese University of Hong Kong Shatin Hong Kong

Department of Tumor Cell Biology St Jude Children's Research Hospital Memphis TN USA

Departments of Neuroscience Washington University School of Medicine in St Louis St Louis MO USA

Departments of Pathology Ophthalmology and Oncology John Hopkins University School of Medicine Baltimore MD USA

Departments of Pediatrics and Human Genetics McGill University Montreal Quebec Canada

Developmental and Stem Cell Biology Program The Hospital for Sick Children Toronto Ontario Canada

Developmental Tumor Biology Laboratory Hospital Sant Joan de Déu Esplugues de Llobregat Barcelona Spain

Dipartimento di Medicina Molecolare e Biotecnologie Mediche University of Naples Federico 2 Naples Italy

Division of Brain Tumor Translational Research National Cancer Center Research Institute Tokyo Japan

Division of Haematology Oncology Department of Pediatrics The Hospital for Sick Children Toronto Ontario Canada

Division of Neurosurgery Centro Hospitalar Lisboa Norte Hospital de Santa Maria Lisbon Portugal

Division of Neurosurgery The Hospital for Sick Children Toronto Ontario Canada

Division of Pediatric Hematology Oncology Hospital Pediatría Centro Médico Nacional century XXI Mexico City Mexico

Division of Pediatric Hematology Oncology Mayo Clinic Rochester MN USA

Division of Pediatric Neurooncology German Cancer Research Center Heidelberg Germany

Division of Pediatric Neurosurgery Case Western Reserve Cleveland OH USA

Division of Pediatric Oncology and Hematology Department of Women Child and Adolescent University Geneva Hospitals Geneva Switzerland

Division of Stem Cell Research Institute for Clinical Research Osaka National Hospital Osaka Japan

Fondazione IRCCS Istituto Nazionale Tumori Milan Italy

INSERM U1028 CNRS UMR5292 Centre de Recherche en Neurosciences Université de Lyon Lyon France

INSERM U830 Institut Curie Paris France

INSERM U900 Institut Curie Paris France

Instituto de Medicina Molecular João Lobo Antunes Faculdade de Medicina Universidade de Lisboa Lisbon Portugal

Instituto Nacional De Pediatría de México Mexico City Mexico

Lady Davis Research Institute Jewish General Hospital Montreal Quebec Canada

McGill University Genome Centre McGill University Montreal Quebec Canada

Pediatrics Virginia Commonwealthy University School of Medicine Richmond VA USA

Princess Margaret Cancer Centre University Health Network Toronto Ontario Canada

PSL Research University Institut Curie Paris France

PSL Research University Université Paris Sud Université Paris Saclay CNRS UMR 3347 INSERM U1021 Institut Curie Orsay France

SIREDO Oncology Center Institut Curie Paris France

Surgical Pathology Unit San Camillo Forlanini Hospital Rome Italy

The Arthur and Sonia Labatt Brain Tumor Research Centre The Hospital for Sick Children Toronto Ontario Canada

The Research Institute of the McGill University Health Center Montreal Quebec Canada

Tumor Initiation and Maintenance Program NCI Designated Cancer Center Sanford Burnham Prebys Medical Discovery Institute La Jolla CA USA

U O Neurochirurgia Istituto Giannina Gaslini Genova Italy

Unit of Somatic Genetics Institut Curie Paris France

Université Paris Cité Paris France

UPMC Hillman Cancer Center Pittsburgh PA USA

Komentář v

Nature. 2022 Sep;609(7929):901-903. doi: 10.1038/d41586-022-02951-x. PubMed

Erratum v

Nature. 2022 Dec;612(7940):E12. doi: 10.1038/s41586-022-05578-0. PubMed

Zobrazit více v PubMed

Northcott PA et al. Medulloblastoma Comprises Four Distinct Molecular Variants. J. Clin. Oncol 29, 1408–1414 (2011). PubMed PMC

Cavalli FMG et al. Intertumoral Heterogeneity within Medulloblastoma Subgroups. Cancer Cell 31, 737–754.e6 (2017). PubMed PMC

Vladoiu MC et al. Childhood cerebellar tumors mirror conserved fetal transcriptional programs. Nature 350280 (2019). PubMed PMC

Hovestadt V. et al. Resolving medulloblastoma cellular architecture by single-cell genomics. Nature 572, 74–79 (2019). PubMed PMC

Wechsler-Reya RJ & Scott MP Control of Neuronal Precursor Proliferation in the Cerebellum by Sonic Hedgehog. Neuron 22, 103–114 (1999). PubMed

Wallace VA Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr. Biol 9, 445–448 (1999). PubMed

Yang Z-J et al. Medulloblastoma Can Be Initiated by Deletion of Patched in Lineage-Restricted Progenitors or Stem Cells. Cancer Cell 14, 135–145 (2008). PubMed PMC

Oliver TG et al. Loss of patched and disruption of granule cell development in a pre-neoplastic stage of medulloblastoma. Development 132, 2425–2439 (2005). PubMed

Gibson P. et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 468, 1095–1099 (2010). PubMed PMC

Jessa S. et al. Stalled developmental programs at the root of pediatric brain tumors. Nat. Genet 51, 1702–1713 (2019). PubMed PMC

Northcott PA et al. The whole-genome landscape of medulloblastoma subtypes. Nature 547, 311–317 (2017). PubMed PMC

Haldipur P. et al. Spatiotemporal expansion of primary progenitor zones in the developing human cerebellum. Science (80-. ). 366, 454–460 (2019). PubMed PMC

Aldinger KA et al. Spatial and cell type transcriptional landscape of human cerebellar development. Nat. Neurosci 24, 1163–1175 (2021). PubMed PMC

Juraschka K. & Taylor MD Medulloblastoma in the age of molecular subgroups: a review. J. Neurosurg. Pediatr 24, 353–363 (2019). PubMed

Tu S. et al. Co-repressor CBFA2T2 regulates pluripotency and germline development. Nature 534, 387–390 (2016). PubMed PMC

Nady N. et al. ETO family protein Mtgr1 mediates Prdm14 functions in stem cell maintenance and primordial germ cell formation. Elife 4, (2015). PubMed PMC

Tracey LJ et al. The Pluripotency Regulator PRDM14 Requires Hematopoietic Regulator CBFA2T3 to Initiate Leukemia in Mice. Mol. Cancer Res 17, 1468–1479 (2019). PubMed PMC

Baulies A. et al. The Transcription Co-Repressors MTG8 and MTG16 Regulate Exit of Intestinal Stem Cells From Their Niche and Differentiation Into Enterocyte vs Secretory Lineages. Gastroenterology 159, 1328–1341.e3 (2020). PubMed PMC

Stadhouders R. et al. Control of developmentally primed erythroid genes by combinatorial co-repressor actions. Nat. Commun 6, 8893 (2015). PubMed PMC

Northcott PA et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 488, 49–56 (2012). PubMed PMC

Waszak SM et al. Germline Elongator mutations in Sonic Hedgehog medulloblastoma. Nature 580, 396–401 (2020). PubMed PMC

Badodi S. et al. Convergence of BMI1 and CHD7 on ERK Signaling in Medulloblastoma. Cell Rep. 21, 2772–2784 (2017). PubMed PMC

Skowron P. et al. The transcriptional landscape of Shh medulloblastoma. Nat. Commun 12, 1749 (2021). PubMed PMC

Parang B. et al. The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation. FASEB J. 29, 786–795 (2015). PubMed PMC

Branon TC et al. Efficient proximity labeling in living cells and organisms with TurboID. Nat. Biotechnol 36, 880–887 (2018). PubMed PMC

Forget A. et al. Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling. Cancer Cell 34, 379–395.e7 (2018). PubMed

Linggi B. & Carpenter G. ErbB-4 s80 Intracellular Domain Abrogates ETO2-dependent Transcriptional Repression. J. Biol. Chem 281, 25373–25380 (2006). PubMed

Northcott PA et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511, 428–434 (2014). PubMed PMC

Haldipur P. et al. Evidence of disrupted rhombic lip development in the pathogenesis of Dandy–Walker malformation. Acta Neuropathol. 142, 761–776 (2021). PubMed PMC

Haldipur P. et al. Expression of Sonic Hedgehog During Cell Proliferation in the Human Cerebellum. Stem Cells Dev. 21, 1059–1068 (2012). PubMed

Englund C. Unipolar Brush Cells of the Cerebellum Are Produced in the Rhombic Lip and Migrate through Developing White Matter. J. Neurosci 26, 9184–9195 (2006). PubMed PMC

Leto K. et al. Consensus Paper: Cerebellar Development. The Cerebellum 15, 789–828 (2016). PubMed PMC

Stromecki M. et al. Characterization of a novel OTX2-driven stem cell program in Group 3 and Group 4 medulloblastoma. Mol. Oncol 12, 495–513 (2018). PubMed PMC

Zagozewski J. et al. An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate. Nat. Commun 11, 3627 (2020). PubMed PMC

Brzustowicz RJ Cell rests in the region of the fourth ventricle. AMA Arch. Neurol. Psychiatry 67, 592 (1952). PubMed

Raaf J. Relation of abnormal collections of cells in posterior medullary velum of cerebellum to origin of medulloblastoma. Arch. Neurol. Psychiatry 52, 163 (1944).

Rorke LB, Fogelson MH & Riggs HE Cerebellar heterotopia in infancy. Dev. Med. Child Neurol 10, 644–650 (1968). PubMed

Yachnis AT, Rorke LB & Trojanowski JQ Cerebellar dysplasias in humans: development and possible relationship to glial and primitive neuroectodermal tumors of the cerebellar vermis. J. Neuropathol. Exp. Neurol 53, 61–71 (1994). PubMed

Yang J. & Zhang Y. I-TASSER server: new development for protein structure and function predictions. Nucleic Acids Res. 43, W174–W181 (2015). PubMed PMC

Mermel CH et al. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 12, R41 (2011). PubMed PMC

Canisius S, Martens JWM & Wessels LFA A novel independence test for somatic alterations in cancer shows that biology drives mutual exclusivity but chance explains most co-occurrence. Genome Biol. 17, 261 (2016). PubMed PMC

Finak G. et al. MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biol. 16, 278 (2015). PubMed PMC

Ximerakis M. et al. Single-cell transcriptomic profiling of the aging mouse brain. Nat. Neurosci (2019). doi:10.1038/s41593-019-0491-3 PubMed DOI

Aibar S. et al. SCENIC: single-cell regulatory network inference and clustering. Nat. Methods 14, 1083–1086 (2017). PubMed PMC

Love MI, Huber W. & Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014). PubMed PMC

Milde T. et al. HD-MB03 is a novel Group 3 medulloblastoma model demonstrating sensitivity to histone deacetylase inhibitor treatment. J. Neurooncol 110, 335–348 (2012). PubMed

Dietl S. et al. MB3W1 is an orthotopic xenograft model for anaplastic medulloblastoma displaying cancer stem cell- and Group 3-properties. BMC Cancer 16, 115 (2016). PubMed PMC

Choi H. et al. SAINT: probabilistic scoring of affinity purification–mass spectrometry data. Nat. Methods 8, 70–73 (2011). PubMed PMC

Teo G. et al. SAINTexpress: Improvements and additional features in Significance Analysis of INTeractome software. J. Proteomics 100, 37–43 (2014). PubMed PMC

Chen S, Zhou Y, Chen Y. & Gu J. fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 34, i884–i890 (2018). PubMed PMC

Patro R, Duggal G, Love MI, Irizarry RA & Kingsford C. Salmon provides fast and bias-aware quantification of transcript expression. Nat. Methods 14, 417–419 (2017). PubMed PMC

Suzuki H. et al. Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma. Nature 574, 707–711 (2019). PubMed PMC

Auwera GA et al. From FastQ Data to High-Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline. Curr. Protoc. Bioinforma 43, (2013). PubMed PMC

Wang K, Li M. & Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164–e164 (2010). PubMed PMC

Lawrence MS et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013). PubMed PMC

Mularoni L, Sabarinathan R, Deu-Pons J, Gonzalez-Perez A. & López-Bigas N. OncodriveFML: a general framework to identify coding and non-coding regions with cancer driver mutations. Genome Biol. 17, 128 (2016). PubMed PMC

Haas BJ et al. Accuracy assessment of fusion transcript detection via read-mapping and de novo fusion transcript assembly-based methods. Genome Biol. 20, 213 (2019). PubMed PMC

Okonechnikov K. et al. InFusion: Advancing Discovery of Fusion Genes and Chimeric Transcripts from Deep RNA-Sequencing Data. PLoS One 11, e0167417 (2016). PubMed PMC

Robertson G. et al. De novo assembly and analysis of RNA-seq data. Nat. Methods 7, 909–912 (2010). PubMed

Zheng GXY et al. Massively parallel digital transcriptional profiling of single cells. Nat. Commun 8, 14049 (2017). PubMed PMC

Hao Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587.e29 (2021). PubMed PMC

Hafemeister C. & Satija R. Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression. Genome Biol. 20, 296 (2019). PubMed PMC

Patel AP et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science (80-. ). 344, 1396–1401 (2014). PubMed PMC

Khazaei S. et al. H3.3 G34W Promotes Growth and Impedes Differentiation of Osteoblast-Like Mesenchymal Progenitors in Giant Cell Tumor of Bone. Cancer Discov. 10, 1968–1987 (2020). PubMed PMC

Street K. et al. Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics 19, 477 (2018). PubMed PMC

Angerer P. et al. destiny : diffusion maps for large-scale single-cell data in R. Bioinformatics 32, 1241–1243 (2016). PubMed

Aran D. et al. Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat. Immunol 20, 163–172 (2019). PubMed PMC

Kowalczyk MS et al. Single-cell RNA-seq reveals changes in cell cycle and differentiation programs upon aging of hematopoietic stem cells. Genome Res. 25, 1860–1872 (2015). PubMed PMC

Vanner RJ et al. Quiescent Sox2+ Cells Drive Hierarchical Growth and Relapse in Sonic Hedgehog Subgroup Medulloblastoma. Cancer Cell 26, 33–47 (2014). PubMed PMC

Newman AM et al. Robust enumeration of cell subsets from tissue expression profiles. Nat. Methods 12, 453–457 (2015). PubMed PMC

Van de Sande B. et al. A scalable SCENIC workflow for single-cell gene regulatory network analysis. Nat. Protoc 15, 2247–2276 (2020). PubMed

Nagy C. et al. Single-nucleus transcriptomics of the prefrontal cortex in major depressive disorder implicates oligodendrocyte precursor cells and excitatory neurons. Nat. Neurosci 23, 771–781 (2020). PubMed

Gulati GS et al. Single-cell transcriptional diversity is a hallmark of developmental potential. Science (80-. ). 367, 405–411 (2020). PubMed PMC

Van den Berge K. et al. Trajectory-based differential expression analysis for single-cell sequencing data. Nat. Commun 11, 1201 (2020). PubMed PMC

Therneau T. A Package for Survival Analysis in R. (2021).

Wei Y. et al. A TAF4-homology domain from the corepressor ETO is a docking platform for positive and negative regulators of transcription. Nat. Struct. Mol. Biol 14, 653–661 (2007). PubMed

Szklarczyk D. et al. The STRING database in 2021: customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 49, D605–D612 (2021). PubMed PMC

Merico D, Isserlin R, Stueker O, Emili A. & Bader GD Enrichment Map: A Network-Based Method for Gene-Set Enrichment Visualization and Interpretation. PLoS One 5, e13984 (2010). PubMed PMC

Shannon P. Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks. Genome Res. 13, 2498–2504 (2003). PubMed PMC

Gu Z, Eils R. & Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics 32, 2847–2849 (2016). PubMed

Zhou X. et al. Exploring genomic alteration in pediatric cancer using ProteinPaint. Nat. Genet 48, 4–6 (2016). PubMed PMC

Penas C. et al. Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis. Nat. Commun 10, 3028 (2019). PubMed PMC

Reimand J, Kull M, Peterson H, Hansen J. & Vilo J. g:Profiler—a web-based toolset for functional profiling of gene lists from large-scale experiments. Nucleic Acids Res. 35, W193–W200 (2007). PubMed PMC