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Failure of human rhombic lip differentiation underlies medulloblastoma formation.

Liam D HendrikseParthiv HaldipurOlivier SaulnierJake MillmanAlexandria H SjoboenAnders Wilder EricksonWinnie OngVictor GordonLudivine Coudière-MorrisonAudrey L MercierMohammad ShokouhianRaúl A SuárezMichelle LyStephanie BorlaseDavid S ScottMaria C VladoiuHamza FarooqOlga SirbuTakuma NakashimaShohei NambuYusuke FunakoshiAlec BahcheliJ Javier Diaz-MejiaJoseph GolserKathleen BachTram Phuong-BaoPatryk SkowronEvan Y WangSachin A KumarPolina BalinAbhirami VisvanathanJohn J Y LeeRamy AyoubXin ChenXiaodi ChenKaren L MungallBetty LuuPierre BérubéYu C WangStefan M PfisterSeung-Ki KimOlivier O DelattreFranck BourdeautFrançois DozJulien Masliah-PlanchonWieslawa A GrajkowskaJames LoukidesPeter B DirksMichelle Fèvre-MontangeAnne JouvetPim J FrenchJohan M KrosKarel ZitterbartSwneke D BaileyCharles G EberhartAmulya A N RaoCaterina GianniniJames M OlsonMiklós GaramiPeter HauserJoanna J PhillipsYoung S RaCarmen de TorresJaume MoraKay K W LiHo-Keung NgWai S PoonIan F PollackEnrique López-AguilarG Yancey GillespieTimothy E Van MeterTomoko ShofudaRajeev VibhakarReid C ThompsonMichael K CooperJoshua B RubinToshihiro KumabeShin JungBoleslaw LachAchille IolasconVeronica FerrucciPasqualino de AntonellisMassimo ZolloGiuseppe CinalliShenandoah RobinsonDuncan S StearnsErwin G Van MeirPaola PorratiGaetano FinocchiaroMaura MassiminoCarlos G CarlottiClaudia C FariaMartine F RousselFrederick BoopJennifer A ChanKimberly A AldingerFerechte RazaviEvelina SilvestriRoger E McLendonEric Michael ThompsonMarc AnsariMaria L GarreFernando ChicoPilar EguíaMario PérezpeñaA Sorana MorrissyFlorence M G CavalliXiaochong WuCraig DanielsJeremy N RichSteven J M JonesRichard A MooreMarco A MarraXi HuangJüri ReimandPoul H SorensenRobert J Wechsler-ReyaWilliam A WeissTrevor J PughLivia GarziaClaudia L KleinmanLincoln D SteinNada JabadoDavid MalkinOlivier AyraultJeffrey A GoldenDavid W EllisonBradley W DobleVijay RamsawamiTamra E Werbowetski-OgilvieHiromichi SuzukiKathleen J MillenMichael D Taylor
Published in: Nature (2022)
Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1-4 . Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5-8 . By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10 . However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4 . 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.
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