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Failure of human rhombic lip differentiation underlies medulloblastoma formation

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HENDRIKSE Liam D HALDIPUR Parthiv SAULNIER Olivier MILLMAN Jake SJOBOEN Alexandria H ERICKSON Anders W ONG Winnie GORDON Victor COUDIERE-MORRISON Ludivine MERCIER Audrey L SHOKOUHIAN Mohammad SUAREZ Raul A LY Michelle BORLASE Stephanie SCOTT David S VLADOIU Maria C FAROOQ Hamza SIRBU Olga NAKASHIMA Takuma NAMBU Shohei FUNAKOSHI Yusuke BAHCHELI Alec DIAZ-MEJIA J Javier GOLSER Joseph BACH Kathleen PHUONG-BAO Tram SKOWRON Patryk WANG Evan Y KUMAR Sachin A BALIN Polina VISVANATHAN Abhirami LEE John J Y AYOUB Ramy CHEN Xin CHEN Xiaodi MUNGALL Karen L LUU Betty BERUBE Pierre WANG Yu C PFISTER Stefan M KIM Seung-Ki DELATTRE Olivier BOURDEAUT Franck DOZ Francois MASLIAH-PLANCHON Julien GRAJKOWSKA Wieslawa A LOUKIDES James DIRKS Peter FEVRE-MONTANGE Michelle JOUVET Anne FRENCH Pim J KROS Johan M ZITTERBART Karel BAILEY Swneke D EBERHART Charles G RAO Amulya A N GIANNINI Caterina OLSON James M GARAMI Miklos HAUSER Peter PHILLIPS Joanna J RA Young S CARMEN de Torres MORA Jaume LI Kay K W NG Ho-Keung POON Wai S POLLACK Ian F LOPEZ-AGUILAR Enrique GILLESPIE G Yancey VAN METER TIMOTHY E. SHOFUDA Tomoko VIBHAKAR Rajeev THOMPSON Reid C COOPER Michael K RUBIN Joshua B KUMABE Toshihiro JUNG Shin LACH Boleslaw LOLASCON Achille FERRUCCI Veronica PASQUALINO de Antonellis ZOLLO Massimo CINALLI Giuseppe ROBINSON Shenandoah STEARNS Duncan S VAN MEIR ERWIN G. PORRATI Paola FINOCCHIARO Gaetano MASSIMINO Maura CARLOTTI Carlos G FARIA Claudia C ROUSSEL Martine F BOOP Frederick CHAN Jennifer A ALDINGER Kimberly A RAZAVI Ferechte SILVESTRI Evelina MCLENDON Roger E THOMPSON Eric M ANSARI Marc GARRE Maria L CHICO Fernando EGUIA Pilar PEREZPENA Mario MORRISSY A Sorana CAVALLI Florence M G WU Xiaochong DANIELS Craig RICH Jeremy N JONES Steven J M MOORE Richard A MARRA Marco A HUANG Xi REIMAND Juri SORENSEN Poul H WECHSLER-REYA Robert J WEISS William A PUGH Trevor J GARZIA Livia KLEINMAN Claudia L STEIN Lincoln D JABADO Nada MALKIN David AYRAULT Olivier GOLDEN Jeffrey A ELLISON David W DOBLE Brad RAMASWAMY Vijay WERBOWETSKI-OGILVIE Tamra E SUZUKI Hiromichi MILLEN Kathleen J TAYLOR Michael D

Rok publikování 2022
Druh Článek v odborném periodiku
Časopis / Zdroj Nature
Fakulta / Pracoviště MU

Lékařská fakulta

Citace
www https://www.nature.com/articles/s41586-022-05215-w
Doi http://dx.doi.org/10.1038/s41586-022-05215-w
Klíčová slova human rhombic lip; failure; medulloblastoma formation
Popis Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong linksto 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, mutationsthat activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurringgroup 4 (G4) MB, which isthought to arise in the unipolar brush cell lineage(3,4). Here we demonstrate that somatic mutationsthat 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 ofthe cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2in model systems relieves this differentiation blockade, which allows MB cellsto spontaneously proceed along normal developmental differentiation trajectories. The specific nature ofthe split human RL, which is destined togenerate most ofthe neurons in the human brain, and its high level of susceptible EOMES(+)K167(+) unipolar brush cell progenitor cells probably predisposes our speciesto the development of G4 MB.

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