| Literature DB >> 36131014 |
Liam D Hendrikse1,2,3, Parthiv Haldipur4, Olivier Saulnier1,2, Jake Millman4, Alexandria H Sjoboen4, Anders W Erickson1,2,5, Winnie Ong1,2,5, Victor Gordon6, Ludivine Coudière-Morrison6, Audrey L Mercier7, Mohammad Shokouhian8, Raúl A Suárez1,2, Michelle Ly1,2,5, Stephanie Borlase6, David S Scott1,2, Maria C Vladoiu1,2,5, Hamza Farooq1,2,5, Olga Sirbu1,2,3, Takuma Nakashima9, Shohei Nambu9, Yusuke Funakoshi9, Alec Bahcheli10,11, J Javier Diaz-Mejia12, Joseph Golser4, Kathleen Bach4, Tram Phuong-Bao8, Patryk Skowron1,2,5, Evan Y Wang1,2,3, Sachin A Kumar1,2,5, Polina Balin1,2,5, Abhirami Visvanathan1,2, John J Y Lee1,2,5, Ramy Ayoub3, Xin Chen1,2, Xiaodi Chen1,2, Karen L Mungall13, Betty Luu1,2, Pierre Bérubé14, Yu C Wang14, Stefan M Pfister15,16, Seung-Ki Kim17, Olivier Delattre18,19, Franck Bourdeaut18,19, François Doz18,20, Julien Masliah-Planchon21, Wieslawa A Grajkowska22, James Loukides1, Peter Dirks1,2,10,23, Michelle Fèvre-Montange24,25, Anne Jouvet25, Pim J French26, Johan M Kros27, Karel Zitterbart28, Swneke D Bailey29,30, Charles G Eberhart31, Amulya A N Rao32, Caterina Giannini33, James M Olson34, Miklós Garami35, Peter Hauser35, Joanna J Phillips36,37, Young S Ra38, Carmen de Torres39, Jaume Mora39, Kay K W Li40, Ho-Keung Ng40, Wai S Poon41, Ian F Pollack42, Enrique López-Aguilar43, G Yancey Gillespie44, Timothy E Van Meter45, Tomoko Shofuda46, Rajeev Vibhakar47, Reid C Thompson48, Michael K Cooper49, Joshua B Rubin50, Toshihiro Kumabe51, Shin Jung52, Boleslaw Lach53,54, Achille Lolascon55,56, Veronica Ferrucci55,56, Pasqualino de Antonellis55,56, Massimo Zollo55,56, Giuseppe Cinalli57, Shenandoah Robinson58, Duncan S Stearns59, Erwin G Van Meir60, Paola Porrati61, Gaetano Finocchiaro61, Maura Massimino61, Carlos G Carlotti62, Claudia C Faria63,64, Martine F Roussel65, Frederick Boop65, Jennifer A Chan66, Kimberly A Aldinger4,67, Ferechte Razavi68, Evelina Silvestri69, Roger E McLendon70,71, Eric M Thompson71, Marc Ansari72,73, Maria L Garre74, Fernando Chico75, Pilar Eguía75, Mario Pérezpeña76, A Sorana Morrissy66,77,78, Florence M G Cavalli79,80,81, Xiaochong Wu1,2, Craig Daniels1,2, Jeremy N Rich82, Steven J M Jones13,83,84, Richard A Moore13, Marco A Marra13,83, Xi Huang1,2,10, Jüri Reimand3,10,11, Poul H Sorensen85,86, Robert J Wechsler-Reya87, William A Weiss36,88,89, Trevor J Pugh3,11,12, Livia Garzia90, Claudia L Kleinman91,92, Lincoln D Stein10,93, Nada Jabado94,95, David Malkin3,96, Olivier Ayrault7, Jeffrey A Golden97, David W Ellison98, Brad Doble8, Vijay Ramaswamy1,2,3,96, Tamra E Werbowetski-Ogilvie6,99, Hiromichi Suzuki9, Kathleen J Millen4, Michael D Taylor100,101,102,103,104.
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.Entities:
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Year: 2022 PMID： 36131014 DOI： 10.1038/s41586-022-05215-w
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 69.504