Failure of human rhombic lip differentiation underlies medulloblastoma formation

Liam D. Hendrikse, Parthiv Haldipur, Olivier Saulnier, Jake Millman, Alexandria H. Sjoboen, Anders W. Erickson, Winnie Ong, Victor Gordon, Ludivine Coudière-Morrison, Audrey L. Mercier, Mohammad Shokouhian, Raúl A. Suárez, Michelle Ly, Stephanie Borlase, David S. Scott, Maria C. Vladoiu, Hamza Farooq, Olga Sirbu, Takuma Nakashima, Shohei Nambu, Yusuke Funakoshi, Alec Bahcheli, J. Javier Diaz-Mejia, Joseph Golser, Kathleen Bach, Tram Phuong-Bao, Patryk Skowron, Evan Y. Wang, Sachin A. Kumar, Polina Balin, Abhirami Visvanathan, John J. Y. Lee, Ramy Ayoub, Xin Chen, Xiaodi Chen, Karen L. Mungall, Betty Luu, Pierre Bérubé, Yu C. Wang, Stefan M. Pfister, Seung-Ki Kim, Olivier Delattre, Franck Bourdeaut, François Doz, Julien Masliah-Planchon, Wieslawa A. Grajkowska, James Loukides, Peter Dirks, Michelle Fèvre-Montange, Anne Jouvet, Pim J. French, Johan M. Kros, Karel Zitterbart, Swneke D. Bailey, Charles G. Eberhart, Amulya A. N. Rao, Caterina Giannini, James M. Olson, Miklós Garami, Peter Hauser, Joanna J. Phillips, Young S. Ra, Carmen Torres, Jaume Mora, Kay K. W. Li, Ho-Keung Ng, Wai S. Poon, Ian F. Pollack, Enrique López-Aguilar, G. Yancey Gillespie, Timothy E. Meter, Tomoko Shofuda, Rajeev Vibhakar, Reid C. Thompson, Michael K. Cooper, Joshua B. Rubin, Toshihiro Kumabe, Shin Jung, Boleslaw Lach, Achille Iolascon, Veronica Ferrucci, Pasqualino Antonellis, Massimo Zollo, Giuseppe Cinalli, Shenandoah Robinson, Duncan S. Stearns, Erwin G. Meir, Paola Porrati, Gaetano Finocchiaro, Maura Massimino, Carlos G. Carlotti, Claudia C. Faria, Martine F. Roussel, Frederick Boop, Jennifer A. Chan, Kimberly A. Aldinger, Ferechte Razavi, Evelina Silvestri, Roger E. McLendon, Eric M. Thompson, Marc Ansari, Maria L. Garre, Fernando Chico, Pilar Eguía, Mario Pérezpeña, A. Sorana Morrissy, Florence M. G. Cavalli, Xiaochong Wu, Craig Daniels, Jeremy N. Rich, Steven J. M. Jones, Richard A. Moore, Marco A. Marra, Xi Huang, Jüri Reimand, Poul H. Sorensen, Robert J. Wechsler-Reya, William A. Weiss, Trevor J. Pugh, Livia Garzia, Claudia L. Kleinman, Lincoln D. Stein, Nada Jabado, David Malkin, Olivier Ayrault, Jeffrey A. Golden, David W. Ellison, Brad Doble, Vijay Ramaswamy, Tamra E. Werbowetski-Ogilvie, Hiromichi Suzuki, Kathleen J. Millen and Michael D. Taylor ()
Additional contact information
Liam D. Hendrikse: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Parthiv Haldipur: Center for Integrative Brain Research, Seattle Children’s Research Institute
Olivier Saulnier: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Jake Millman: Center for Integrative Brain Research, Seattle Children’s Research Institute
Alexandria H. Sjoboen: Center for Integrative Brain Research, Seattle Children’s Research Institute
Anders W. Erickson: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Winnie Ong: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Victor Gordon: University of Manitoba
Ludivine Coudière-Morrison: University of Manitoba
Audrey L. Mercier: PSL Research University, Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Institut Curie
Mohammad Shokouhian: University of Manitoba
Raúl A. Suárez: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Michelle Ly: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Stephanie Borlase: University of Manitoba
David S. Scott: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Maria C. Vladoiu: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Hamza Farooq: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Olga Sirbu: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Takuma Nakashima: Division of Brain Tumor Translational Research, National Cancer Center Research Institute
Shohei Nambu: Division of Brain Tumor Translational Research, National Cancer Center Research Institute
Yusuke Funakoshi: Division of Brain Tumor Translational Research, National Cancer Center Research Institute
Alec Bahcheli: University of Toronto
J. Javier Diaz-Mejia: University Health Network
Joseph Golser: Center for Integrative Brain Research, Seattle Children’s Research Institute
Kathleen Bach: Center for Integrative Brain Research, Seattle Children’s Research Institute
Tram Phuong-Bao: University of Manitoba
Patryk Skowron: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Evan Y. Wang: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Sachin A. Kumar: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Polina Balin: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Abhirami Visvanathan: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
John J. Y. Lee: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Ramy Ayoub: University of Toronto
Xin Chen: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Xiaodi Chen: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Karen L. Mungall: Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency
Betty Luu: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Pierre Bérubé: McGill University Genome Centre, McGill University
Yu C. Wang: McGill University Genome Centre, McGill University
Stefan M. Pfister: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ)
Seung-Ki Kim: Seoul National University Children’s Hospital
Olivier Delattre: SIREDO Oncology Center (Pediatric, Adolescent and Young Adults Oncology), Institut Curie
Franck Bourdeaut: SIREDO Oncology Center (Pediatric, Adolescent and Young Adults Oncology), Institut Curie
François Doz: SIREDO Oncology Center (Pediatric, Adolescent and Young Adults Oncology), Institut Curie
Julien Masliah-Planchon: Unit of Somatic Genetics, Institut Curie
Wieslawa A. Grajkowska: The Children’s Memorial Health Institute
James Loukides: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Peter Dirks: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Michelle Fèvre-Montange: INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences, Université de Lyon
Anne Jouvet: Centre de Pathologie EST, Groupement Hospitalier EST, Université de Lyon
Pim J. French: Erasmus University Medical Center
Johan M. Kros: Erasmus University Medical Center
Karel Zitterbart: Masaryk University School of Medicine
Swneke D. Bailey: McGill University
Charles G. Eberhart: John Hopkins University School of Medicine
Amulya A. N. Rao: Division of Pediatric Hematology/Oncology, Mayo Clinic
Caterina Giannini: Mayo Clinic
James M. Olson: Clinical Research Division, Fred Hutchinson Cancer Research Center
Miklós Garami: Semmelweis University
Peter Hauser: Semmelweis University
Joanna J. Phillips: University of California San Francisco
Young S. Ra: University of Ulsan, Asan Medical Center
Carmen Torres: Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat
Jaume Mora: Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat
Kay K. W. Li: The Chinese University of Hong Kong
Ho-Keung Ng: The Chinese University of Hong Kong
Wai S. Poon: The Chinese University of Hong Kong
Ian F. Pollack: University of Pittsburgh School of Medicine
Enrique López-Aguilar: Division of Pediatric Hematology/Oncology, Hospital Pediatría Centro Médico Nacional century XXI
G. Yancey Gillespie: University of Alabama at Birmingham
Timothy E. Meter: Pediatrics, Virginia Commonwealthy University, School of Medicine
Tomoko Shofuda: Division of Stem Cell Research, Institute for Clinical Research, Osaka National Hospital
Rajeev Vibhakar: University of Colorado Denver
Reid C. Thompson: Vanderbilt Medical Center
Michael K. Cooper: Vanderbilt Medical Center
Joshua B. Rubin: Washington University School of Medicine in St Louis
Toshihiro Kumabe: Kitasato University School of Medicine
Shin Jung: Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School
Boleslaw Lach: McMaster University
Achille Iolascon: University of Naples Federico II
Veronica Ferrucci: University of Naples Federico II
Pasqualino Antonellis: University of Naples Federico II
Massimo Zollo: University of Naples Federico II
Giuseppe Cinalli: Santobono-Pausilipon Children’s Hospital
Shenandoah Robinson: Division of Pediatric Neurosurgery, Case Western Reserve
Duncan S. Stearns: Case Western Reserve
Erwin G. Meir: Emory University School of Medicine and Winship Cancer Institute
Paola Porrati: Fondazione IRCCS Istituto Nazionale Tumori
Gaetano Finocchiaro: Fondazione IRCCS Istituto Nazionale Tumori
Maura Massimino: Fondazione IRCCS Istituto Nazionale Tumori
Carlos G. Carlotti: Faculty of Medicine of Ribeirão Preto, University of São Paulo
Claudia C. Faria: Division of Neurosurgery, Centro Hospitalar Lisboa Norte (CHULN), Hospital de Santa Maria
Martine F. Roussel: St Jude Children’s Research Hospital
Frederick Boop: St Jude Children’s Research Hospital
Jennifer A. Chan: University of Calgary
Kimberly A. Aldinger: Center for Integrative Brain Research, Seattle Children’s Research Institute
Ferechte Razavi: Assistance Publique Hôpitaux de Paris, Hôpital Necker-Enfants Malades
Evelina Silvestri: Surgical Pathology Unit, San Camillo Forlanini Hospital
Roger E. McLendon: Duke University
Eric M. Thompson: Duke University
Marc Ansari: University of Geneva
Maria L. Garre: U.O. Neurochirurgia, Istituto Giannina Gaslini
Fernando Chico: Department of Neurosurgery, Hospital Infantil de Mexico Federico Gomez
Pilar Eguía: Department of Neurosurgery, Hospital Infantil de Mexico Federico Gomez
Mario Pérezpeña: Instituto Nacional De Pediatría de México
A. Sorana Morrissy: University of Calgary
Florence M. G. Cavalli: INSERM U900, Institut Curie
Xiaochong Wu: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Craig Daniels: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Jeremy N. Rich: UPMC Hillman Cancer Center
Steven J. M. Jones: Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency
Richard A. Moore: Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency
Marco A. Marra: Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency
Xi Huang: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Jüri Reimand: University of Toronto
Poul H. Sorensen: University of British Columbia
Robert J. Wechsler-Reya: Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute
William A. Weiss: University of California San Francisco
Trevor J. Pugh: University of Toronto
Livia Garzia: Cancer Research Program, McGill University Health Centre Research Institute
Claudia L. Kleinman: McGill University
Lincoln D. Stein: University of Toronto
Nada Jabado: McGill University
David Malkin: University of Toronto
Olivier Ayrault: PSL Research University, Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Institut Curie
Jeffrey A. Golden: Cedars-Sinai Medical Center
David W. Ellison: St Jude Children’s Research Hospital
Brad Doble: University of Manitoba
Vijay Ramaswamy: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children
Tamra E. Werbowetski-Ogilvie: University of Manitoba
Hiromichi Suzuki: Division of Brain Tumor Translational Research, National Cancer Center Research Institute
Kathleen J. Millen: Center for Integrative Brain Research, Seattle Children’s Research Institute
Michael D. Taylor: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children

Nature, 2022, vol. 609, issue 7929, 1021-1028

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41586-022-05215-w

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