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Failure of human rhombic lip differentiation underlies medulloblastoma formation

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  • 09/19/2025
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Authors
    Liam D Hendrikse, The Hospital for Sick Children, TorontoParthiv Haldipur, Seattle Children’s Research InstituteOlivier Saulnier, The Hospital for Sick Children, TorontoJake Millman, Seattle Children’s Research InstituteAlexandra H Sjoboen, Seattle Children’s Research InstituteAnders W Erickson, The Hospital for Sick Children, TorontoWinnie Ong, The Hospital for Sick Children, TorontoVictor Gordon, University of ManitobaLudivine Coudière-Morrison, University of ManitobaAudrey L Mercier, Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Institut Curie, Orsay, FranceMohammad Shokouhian, University of ManitobaRaúl A Suárez, The Hospital for Sick Children, TorontoMichelle Ly, The Hospital for Sick Children, TorontoStephanie Borlase, University of ManitobaDavid S Scott, The Hospital for Sick Children, TorontoMaria C Vladoiu, The Hospital for Sick Children, TorontoHamza Farooq, The Hospital for Sick Children, TorontoOlga Sirbu, The Hospital for Sick Children, TorontoTakuma Nakashima, National Cancer Center Research Institute, TokyoShohei Nambu, National Cancer Center Research Institute, TokyoYusuke Funakoshi, National Cancer Center Research Institute, TokyoAlec Bahcheli, University of TorontoJavier J Diaz-Mejia, University Health Network, Toronto, Ontario, CanadaJoseph Golser, Seattle Children’s Research InstituteKathleen Bach, Seattle Children’s Research InstituteTram Phuong-Bao, University of ManitobaPatryk Skowron, The Hospital for Sick Children, TorontoEvan Y Wang, The Hospital for Sick Children, TorontoSachin A Kumar, The Hospital for Sick Children, TorontoPolina Balin, The Hospital for Sick Children, TorontoAbhirami Visvanathan, The Hospital for Sick Children, TorontoJohn JY Lee, The Hospital for Sick Children, TorontoRamy Ayoub, University of TorontoXin Chen, The Hospital for Sick Children, TorontoXiaodi Chen, The Hospital for Sick Children, TorontoKaren L Mungall, BC Cancer Agency, VancouverBetty Luu, The Hospital for Sick Children, TorontoPierre Berube, McGill UniversityYu C Wang, McGill UniversityStefan M Pfister, German Cancer Research Center (DKFZ)Seung-Ki Kim, Seoul National University Children’s HospitalOlivier Delattre, SIREDO Oncology Center (pediatric, adolescent and young adults oncology), Institut Curie, Paris, FranceFranck Bourdeaut, SIREDO Oncology Center (pediatric, adolescent and young adults oncology), Institut Curie, Paris, FranceFrançois Doz, SIREDO Oncology Center (pediatric, adolescent and young adults oncology), Institut Curie, Paris, FranceJulien Masliah-Planchon, SIREDO Oncology Center (pediatric, adolescent and young adults oncology), Institut Curie, Paris, FranceWieslawa A Grajkowska, Children’s Memorial Health Institute, Warsaw, PolandJames Loukides, The Hospital for Sick Children, TorontoPeter Dirks, The Hospital for Sick Children, TorontoMichelle Fèvre-Montange, Université de LyonAnne Jouvet, Université de LyonPim J French, Erasmus University Medical CenterJohan M Kros, Erasmus University Medical CenterKarel Zitterbart, Masaryk UniversitySwneke D Bailey, McGill UniversityCharles G Eberhart, Johns Hopkins UniversityAmulya AN Rao, Mayo Clinic, RochesterCaterina Giannini, Mayo Clinic, RochesterJames M Olson, Fred Hutchinson Cancer Research CenterMiklós Garami, Semmelweis UniversityPeter Hauser, Semmelweis UniversityJoanna J Phillips, University of California San FranciscoYoung S Ra, University of UlsanCarmen de Torres, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, SpainJaume Mora, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, SpainKay KW Li, Chinese University of Hong KongHo-Keung Ng, Chinese University of Hong KongWai S Poon, Chinese University of Hong KongIan F Pollack, University of PittsburghEnrique López-Aguilar, Hosp Pediat Ctr Med Nacl Century XXIYancey G Gillespie, University of Alabama BirminghamTimothy E Van Meter, Virginia Commonwealthy UnivTomoko Shofuda, Osaka National HospitalRajeev Vibhakar, University of Colorado DenverReid C Thompson, Vanderbilt Medical Center, NashvilleMichael K Cooper, Vanderbilt Medical Center, NashvilleJoshua B Rubin, Washington UniversiyToshihiro Kumabe, Kitasato UniversityShin Jung, Chonnam National UniversityBoleslaw Lach, McMaster UniversityAchille Lolascon, University of Naples Federico IIVeronica Ferrucci, University of Naples Federico IIPasqualino de Antonellis, University of Naples Federico IIMassimo Zollo, University of Naples Federico IIGiuseppe Cinalli, Santobono Pausilipon Childrens HospShenandoah Robinson, Case Western ReserveDuncan S Stearns, Case Western ReserveErwin Van Meir, Emory UniversityPaola Porrati, Fondazione IRCCS Istituto Nazionale TumoriGaetano Finocchiaro, Fondazione IRCCS Istituto Nazionale TumoriMaura Massimino, Fondazione IRCCS Istituto Nazionale TumoriCarlos G Carlotti, University of São PauloClaudia C Faria, Hospital Santa MariaMartine F Roussel, St. Jude Children’s Research Hospital, MemphisFrederick Boop, St. Jude Children’s Research Hospital, MemphisJennifeer A Chan, University of CalgaryKimberly A Aldinger, Seattle Children’s Research InstituteFerechte Razavi, Hôpital Necker-Enfants MaladesEvelina Silvestri, San Camillo Forlanini Hospital, Rome, ItalyRoger E McLendon, Duke UniversityEric M Thompson, Duke UniversityMarc Ansari, University of GenevaMaria L Garre, Istituto Giannina Gaslini, Genova, ItalyFernando Chico, Hospital Infantil de Mexico Federico Gomez, Mexico CityPilar Eguia, Hospital Infantil de Mexico Federico Gomez, Mexico CityMario Pérezpeña, Instituto Nacional De Pediatría de MéxicoSorana A Morrissy, University of CalgaryFlorence MG Cavalli, INSERM U900, Institut Curie, Paris, FranceXiaochong Wu, The Hospital for Sick Children, TorontoCraig Daniels, The Hospital for Sick Children, TorontoJeremy N Rich, UPMC Hillman Cancer Center, PittsburghSteven JM Jones, BC Cancer AgencyRichard A Moore, BC Cancer AgencyMarco A Marra, BC Cancer AgencyXi Huang, Hosp Sick ChildrenJüri Reimand, University of TorontoPoul H Sorensen, University of British ColumbiaRobert J Wechsler-Reya, Sanford Burnham Prebys Medical Discovery InstituteWilliam A Weiss, University of California San FranciscoTrevor J Pugh, University of TorontoLivia Garzia, McGill University Health Centre Research InstituteClaudia L Kleinman, McGill UniversityLincoln D Stein, University of TorontoNada Jabado, McGill UniversityDavid Malkin, University of TorontoOlivier Ayrault, Université Paris Sud, Université Paris-SaclayJeffrey A Golden, Cedars-Sinai Medical CenterDavid W Ellison, St. Jude Children’s Research HospitalBrad Doble, University of ManitobaVijay Ramaswamy, The Hospital for Sick ChildrenTamra E Werbowetski-Ogilvie, University of ManitobaHiromichi Suzuki, National Cancer Center Research Institute, Tokyo, JapanKathleen J Millen, Seattle Children’s Research InstituteMichael D Taylor, The Hospital for Sick Children
Language
  • English
Date
  • 2022-09-21
Publisher
  • NATURE PORTFOLIO
Publication Version
Copyright Statement
  • © 2022, The Author(s), under exclusive licence to Springer Nature Limited
Final Published Version (URL)
Title of Journal or Parent Work
Volume
  • 609
Issue
  • 7929
Start Page
  • 1021
End Page
  • +
Supplemental Material (URL)
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.
Author Notes
  • Correspondence and request for materials should be addressed to T.E.W.-O., K.J.M., or M.D.T. Human material provided by the Joint MRC/Wellcome (MR/R006237/1) Human Developmental Biology Resource (www.hdbr.org), and the Birth Defects Research Laboratory (NIH-R24-HD000836 to IAG) was covered by a material transfer agreement between SCRI and HDBR/BDRL but samples may be requested directly from the HDBR/BDRL. Michael D. Taylor, The Hospital for Sick Children, 555 University Avenue, M5G1X8, Ontario Canada, Ph: 416-813-6427, mdt.cns@gmail.com
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