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TB-06 MOLECULAR MECHANISM OF BRAIN TUMOUR FORMATION DRIVEN BY SUPRATENTORIAL EPENDYMOMA-SPECIFIC YAP1 FUSION GENES
YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions but not YAP1 wildtype are sufficient to drive malignant transformation of neural progenitors in the developing cerebral cortex in...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213335/ http://dx.doi.org/10.1093/noajnl/vdz039.048 |
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author | Kawauchi, Daisuke Pajtler, Kristian Wei, Yiju Okonechnikov, Konstantin Silva, Patricia Jones, David Hoshino, Mikio Pfister, Stefan Kool, Marcel Li, Wei |
author_facet | Kawauchi, Daisuke Pajtler, Kristian Wei, Yiju Okonechnikov, Konstantin Silva, Patricia Jones, David Hoshino, Mikio Pfister, Stefan Kool, Marcel Li, Wei |
author_sort | Kawauchi, Daisuke |
collection | PubMed |
description | YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions but not YAP1 wildtype are sufficient to drive malignant transformation of neural progenitors in the developing cerebral cortex in mice, and the resulting tumours share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is associated with its oncogenicity and is mediated by the nuclear localization signal of MAMLD1 in a YAP1-Ser127 phosphorylation-independent manner. 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, hypothesizing the important role of these transcription factors in YAP1-MAMLD1-driven tumourigenesis. Indeed, co-immunoprecipitation assays revealed physical interactions of TEADs and NFIA/B with the YAP1 and MAMLD1 domains of the fusion protein, respectively. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumour 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. |
format | Online Article Text |
id | pubmed-7213335 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-72133352020-07-07 TB-06 MOLECULAR MECHANISM OF BRAIN TUMOUR FORMATION DRIVEN BY SUPRATENTORIAL EPENDYMOMA-SPECIFIC YAP1 FUSION GENES Kawauchi, Daisuke Pajtler, Kristian Wei, Yiju Okonechnikov, Konstantin Silva, Patricia Jones, David Hoshino, Mikio Pfister, Stefan Kool, Marcel Li, Wei Neurooncol Adv Abstracts YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions but not YAP1 wildtype are sufficient to drive malignant transformation of neural progenitors in the developing cerebral cortex in mice, and the resulting tumours share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is associated with its oncogenicity and is mediated by the nuclear localization signal of MAMLD1 in a YAP1-Ser127 phosphorylation-independent manner. 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, hypothesizing the important role of these transcription factors in YAP1-MAMLD1-driven tumourigenesis. Indeed, co-immunoprecipitation assays revealed physical interactions of TEADs and NFIA/B with the YAP1 and MAMLD1 domains of the fusion protein, respectively. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumour 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. Oxford University Press 2019-12-16 /pmc/articles/PMC7213335/ http://dx.doi.org/10.1093/noajnl/vdz039.048 Text en © The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Abstracts Kawauchi, Daisuke Pajtler, Kristian Wei, Yiju Okonechnikov, Konstantin Silva, Patricia Jones, David Hoshino, Mikio Pfister, Stefan Kool, Marcel Li, Wei TB-06 MOLECULAR MECHANISM OF BRAIN TUMOUR FORMATION DRIVEN BY SUPRATENTORIAL EPENDYMOMA-SPECIFIC YAP1 FUSION GENES |
title | TB-06 MOLECULAR MECHANISM OF BRAIN TUMOUR FORMATION DRIVEN BY SUPRATENTORIAL EPENDYMOMA-SPECIFIC YAP1 FUSION GENES |
title_full | TB-06 MOLECULAR MECHANISM OF BRAIN TUMOUR FORMATION DRIVEN BY SUPRATENTORIAL EPENDYMOMA-SPECIFIC YAP1 FUSION GENES |
title_fullStr | TB-06 MOLECULAR MECHANISM OF BRAIN TUMOUR FORMATION DRIVEN BY SUPRATENTORIAL EPENDYMOMA-SPECIFIC YAP1 FUSION GENES |
title_full_unstemmed | TB-06 MOLECULAR MECHANISM OF BRAIN TUMOUR FORMATION DRIVEN BY SUPRATENTORIAL EPENDYMOMA-SPECIFIC YAP1 FUSION GENES |
title_short | TB-06 MOLECULAR MECHANISM OF BRAIN TUMOUR FORMATION DRIVEN BY SUPRATENTORIAL EPENDYMOMA-SPECIFIC YAP1 FUSION GENES |
title_sort | tb-06 molecular mechanism of brain tumour formation driven by supratentorial ependymoma-specific yap1 fusion genes |
topic | Abstracts |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213335/ http://dx.doi.org/10.1093/noajnl/vdz039.048 |
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