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EPEN-06. CHARACTERISING THE DEVELOPMENTAL ORIGINS AND TRAJECTORIES OF ZFTA-RELA FUSION EPENDYMOMA IN A NOVEL MOUSE MODEL
Ependymomas driven by the ZFTA-RELA fusion account for >70% of all supratentorial ependymomas. These tumours are now recognised in the WHO classification of CNS tumours and have been associated with a poor prognosis. Seven ZFTA-RELA fusion variants have been described: around two thirds of cases...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10259970/ http://dx.doi.org/10.1093/neuonc/noad073.110 |
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author | Bonner, Sigourney King, Claire Rarhmann, Katherine Wickham Cooper, Elizabeth Katyal, Gunjan Gilbertson, Richard |
author_facet | Bonner, Sigourney King, Claire Rarhmann, Katherine Wickham Cooper, Elizabeth Katyal, Gunjan Gilbertson, Richard |
author_sort | Bonner, Sigourney |
collection | PubMed |
description | Ependymomas driven by the ZFTA-RELA fusion account for >70% of all supratentorial ependymomas. These tumours are now recognised in the WHO classification of CNS tumours and have been associated with a poor prognosis. Seven ZFTA-RELA fusion variants have been described: around two thirds of cases are fusion 1. No spontaneous genetically modified mouse models (GEMMS) have been described and current models require invasive intracranial injection (of transduced cells or RCAS-TVA system). Here we describe the first spontaneous GEMM of ZFTA-RELA fusion-driven ependymoma. Nestin-Flx-STOP-Flx-ZFTA-RELA (Fusion 1) open reading frames were targeted together with luciferase to the Rosa-26 locus. Breeding these mice with Nestin-CreERT2 or Blbp-Cre lines that drive recombination in neural progenitor cells resulted in forebrain tumours that could be tracked with bioluminescence imaging from P20. Tumours displayed NF-kB and L1CAM expression and ZFTA-RELA protein was detected using a novel in-house antibody. Tumours display expression of a known ZFTA-RELA fusion ependymoma transcriptomic signature. ZFTA-RELA tumours can be grown as neurospheres and passaged as allografts in nude mice and respond to irradiation. We provide the first spontaneous GEMM of this important group of ependymomas. Here we present our histologic and transcriptomic developmental timecourse of these tumours, their comparison to the human disease and further understanding of the lineage origins and potential novel targets. |
format | Online Article Text |
id | pubmed-10259970 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-102599702023-06-13 EPEN-06. CHARACTERISING THE DEVELOPMENTAL ORIGINS AND TRAJECTORIES OF ZFTA-RELA FUSION EPENDYMOMA IN A NOVEL MOUSE MODEL Bonner, Sigourney King, Claire Rarhmann, Katherine Wickham Cooper, Elizabeth Katyal, Gunjan Gilbertson, Richard Neuro Oncol Final Category: Ependymoma - EPEN Ependymomas driven by the ZFTA-RELA fusion account for >70% of all supratentorial ependymomas. These tumours are now recognised in the WHO classification of CNS tumours and have been associated with a poor prognosis. Seven ZFTA-RELA fusion variants have been described: around two thirds of cases are fusion 1. No spontaneous genetically modified mouse models (GEMMS) have been described and current models require invasive intracranial injection (of transduced cells or RCAS-TVA system). Here we describe the first spontaneous GEMM of ZFTA-RELA fusion-driven ependymoma. Nestin-Flx-STOP-Flx-ZFTA-RELA (Fusion 1) open reading frames were targeted together with luciferase to the Rosa-26 locus. Breeding these mice with Nestin-CreERT2 or Blbp-Cre lines that drive recombination in neural progenitor cells resulted in forebrain tumours that could be tracked with bioluminescence imaging from P20. Tumours displayed NF-kB and L1CAM expression and ZFTA-RELA protein was detected using a novel in-house antibody. Tumours display expression of a known ZFTA-RELA fusion ependymoma transcriptomic signature. ZFTA-RELA tumours can be grown as neurospheres and passaged as allografts in nude mice and respond to irradiation. We provide the first spontaneous GEMM of this important group of ependymomas. Here we present our histologic and transcriptomic developmental timecourse of these tumours, their comparison to the human disease and further understanding of the lineage origins and potential novel targets. Oxford University Press 2023-06-12 /pmc/articles/PMC10259970/ http://dx.doi.org/10.1093/neuonc/noad073.110 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://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 | Final Category: Ependymoma - EPEN Bonner, Sigourney King, Claire Rarhmann, Katherine Wickham Cooper, Elizabeth Katyal, Gunjan Gilbertson, Richard EPEN-06. CHARACTERISING THE DEVELOPMENTAL ORIGINS AND TRAJECTORIES OF ZFTA-RELA FUSION EPENDYMOMA IN A NOVEL MOUSE MODEL |
title | EPEN-06. CHARACTERISING THE DEVELOPMENTAL ORIGINS AND TRAJECTORIES OF ZFTA-RELA FUSION EPENDYMOMA IN A NOVEL MOUSE MODEL |
title_full | EPEN-06. CHARACTERISING THE DEVELOPMENTAL ORIGINS AND TRAJECTORIES OF ZFTA-RELA FUSION EPENDYMOMA IN A NOVEL MOUSE MODEL |
title_fullStr | EPEN-06. CHARACTERISING THE DEVELOPMENTAL ORIGINS AND TRAJECTORIES OF ZFTA-RELA FUSION EPENDYMOMA IN A NOVEL MOUSE MODEL |
title_full_unstemmed | EPEN-06. CHARACTERISING THE DEVELOPMENTAL ORIGINS AND TRAJECTORIES OF ZFTA-RELA FUSION EPENDYMOMA IN A NOVEL MOUSE MODEL |
title_short | EPEN-06. CHARACTERISING THE DEVELOPMENTAL ORIGINS AND TRAJECTORIES OF ZFTA-RELA FUSION EPENDYMOMA IN A NOVEL MOUSE MODEL |
title_sort | epen-06. characterising the developmental origins and trajectories of zfta-rela fusion ependymoma in a novel mouse model |
topic | Final Category: Ependymoma - EPEN |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10259970/ http://dx.doi.org/10.1093/neuonc/noad073.110 |
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