1. YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis.
- Author
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Pajtler KW, Wei Y, Okonechnikov K, Silva PBG, Vouri M, Zhang L, Brabetz S, Sieber L, Gulley M, Mauermann M, Wedig T, Mack N, Imamura Kawasawa Y, Sharma T, Zuckermann M, Andreiuolo F, Holland E, Maass K, Körkel-Qu H, Liu HK, Sahm F, Capper D, Bunt J, Richards LJ, Jones DTW, Korshunov A, Chavez L, Lichter P, Hoshino M, Pfister SM, Kool M, Li W, and Kawauchi D
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Animals, Brain Neoplasms genetics, Brain Neoplasms pathology, Carcinogenesis genetics, Cell Line, Tumor, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, DNA-Binding Proteins genetics, Ependymoma genetics, Ependymoma pathology, HEK293 Cells, Humans, Mice, NFI Transcription Factors genetics, NIH 3T3 Cells, Neural Stem Cells metabolism, Neural Stem Cells pathology, Nuclear Proteins genetics, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Phosphoproteins genetics, Phosphoproteins metabolism, Transcription Factors genetics, YAP-Signaling Proteins, Adaptor Proteins, Signal Transducing metabolism, Brain Neoplasms metabolism, Carcinogenesis metabolism, DNA-Binding Proteins metabolism, Ependymoma metabolism, NFI Transcription Factors metabolism, Nuclear Proteins metabolism, Transcription Factors metabolism
- Abstract
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.
- Published
- 2019
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