TY  - JOUR
AU  - Pajtler, Kristian
AU  - Wei, Yiju
AU  - Okonechnikov, Konstantin
AU  - Silva, Patricia B G
AU  - Vouri, Mikaella
AU  - Zhang, Lei
AU  - Brabetz, Sebastian
AU  - Sieber, Laura
AU  - Gulley, Melissa
AU  - Mauermann, Monika
AU  - Wedig, Tatjana
AU  - Mack, Norman
AU  - Imamura Kawasawa, Yuka
AU  - Sharma, Tanvi
AU  - Zuckermann, Marc
AU  - Andreiuolo, Felipe
AU  - Holland, Eric
AU  - Maass, Kendra
AU  - Körkel-Qu, Huiqin
AU  - Liu, Hai-Kun
AU  - Sahm, Felix
AU  - Capper, David
AU  - Bunt, Jens
AU  - Richards, Linda J
AU  - Jones, David T W
AU  - Korshunov, Andrey
AU  - Chavez, Lukas
AU  - Lichter, Peter
AU  - Hoshino, Mikio
AU  - Pfister, Stefan
AU  - Kool, Marcel
AU  - Li, Wei
AU  - Kawauchi, Daisuke
TI  - YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis.
JO  - Nature Communications
VL  - 10
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2019-02201
SP  - 3914
PY  - 2019
AB  - YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions are sufficient to drive malignant transformation in mice, and the resulting tumors share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is mediated by MAMLD1 and independent of YAP1-Ser127 phosphorylation. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, suggesting a role for these transcription factors in YAP1-MAMLD1-driven tumorigenesis. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumor induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.
LB  - PUB:(DE-HGF)16
C6  - pmid:31477715
C2  - pmc:PMC6718408
DO  - DOI:10.1038/s41467-019-11884-5
UR  - https://inrepo02.dkfz.de/record/144769
ER  -