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Phenotypic characterization with somatic genome editing and gene transfer reveals the diverse oncogenicity of ependymoma fusion genes
- Source :
- Acta Neuropathologica Communications
- Publication Year :
- 2020
-
Abstract
- Recurrent RELA and YAP1 fusions are intimately associated with tumorigenesis in supratentorial ependymomas. Chromothripsis and focal copy number alterations involving 11q are hallmarks of these tumors. However, it is unknown whether the chromosomal alterations are a direct causal event resulting in fusion transcripts. In addition, the biological significance of the RELA fusion variants and YAP1 fusions is not yet fully characterized. In this study, we generated gene rearrangements on 11q with the CRISPR/Cas9 system and investigated the formation of oncogenic ependymoma fusion genes. Further, we examined the oncogenic potential of RELA fusion variants and YAP1 fusions in a lentiviral gene transfer model. We observed that endogenous RELA fusion events were successfully induced by CRISPR/Cas9-mediated genome rearrangement in cultured cells. In vivo genome editing in mouse brain resulted in the development of ependymoma-like brain tumors that harbored the Rela fusion gene. All RELA fusion variants tested, except a variant lacking the Rel homology domain, were able to induce tumor formation, albeit with different efficacy. Furthermore, expression of YAP1-FAM118B and YAP1-MAMLD1 fusions induced the formation of spindle-cell-like tumors at varying efficacy. Our results indicate that chromosomal rearrangements involving the Rela locus are the causal event for the formation of Rela fusion-driven ependymomas in mice. Furthermore, the type of RELA. fusion might affect the aggressiveness of tumors and that the Rel homology domain is essential for the oncogenic functions of RELA. fusions. The YAP1 fusion genes are also oncogenic when expressed in mice.
- Subjects :
- DNA Copy Number Variations
Carcinogenesis
Locus (genetics)
RELA
Biology
Pathology and Forensic Medicine
Rel homology domain
Fusion gene
Cellular and Molecular Neuroscience
Mice
Genome editing
CRISPR
Animals
Oncogene Fusion
Gene
Cells, Cultured
Adaptor Proteins, Signal Transducing
Brain tumor mouse model
Genetics
Gene Editing
Chromothripsis
Gene rearrangement
Brain Neoplasms
Research
CRISPR/Cas9 system
Gene Transfer Techniques
Transcription Factor RelA
YAP-Signaling Proteins
Supratentorial ependymoma
DNA-Binding Proteins
Phenotype
Ependymoma
Neurology (clinical)
CRISPR-Cas Systems
Transcription Factors
Subjects
Details
- ISSN :
- 20515960
- Volume :
- 8
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Acta neuropathologica communications
- Accession number :
- edsair.doi.dedup.....69cda6bd58fe039d61426c5d623eaf40