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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 <jats:italic>RELA<\/jats:italic> fusion variants and Y<jats:italic>AP1<\/jats:italic> 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 <jats:italic>RELA<\/jats:italic> fusion variants and <jats:italic>YAP1<\/jats:italic> fusions in a lentiviral gene transfer model. We observed that endogenous <jats:italic>RELA<\/jats:italic> 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 <jats:italic>Rela<\/jats:italic> fusion gene. All <jats:italic>RELA<\/jats:italic> fusion variants tested, except a variant lacking the Rel homology domain, were able to induce tumor formation, albeit with different efficacy. Furthermore, expression of <jats:italic>YAP1<\/jats:italic>-<jats:italic>FAM118B<\/jats:italic> and <jats:italic>YAP1<\/jats:italic>-<jats:italic>MAMLD1<\/jats:italic> fusions induced the formation of spindle-cell-like tumors at varying efficacy. Our results indicate that chromosomal rearrangements involving the <jats:italic>Rela<\/jats:italic> locus are the causal event for the formation of <jats:italic>Rela<\/jats:italic> fusion-driven ependymomas in mice. Furthermore, the type of <jats:italic>RELA.<\/jats:italic> fusion might affect the aggressiveness of tumors and that the Rel homology domain is essential for the oncogenic functions of <jats:italic>RELA.<\/jats:italic> fusions. The <jats:italic>YAP1<\/jats:italic> fusion genes are also oncogenic when expressed in mice.<\/jats:p>","DOI":"10.1186\/s40478-020-01080-8","type":"journal-article","created":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T15:10:21Z","timestamp":1606144221000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Phenotypic characterization with somatic genome editing and gene transfer reveals the diverse oncogenicity of ependymoma fusion genes"],"prefix":"10.1186","volume":"8","author":[{"given":"Mutsumi","family":"Takadera","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaishi","family":"Satomi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Szulzewsky","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick J.","family":"Cimino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric C.","family":"Holland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuya","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichi","family":"Ichimura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuya","family":"Ozawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,11,23]]},"reference":[{"key":"1080_CR1","doi-asserted-by":"publisher","first-page":"1603","DOI":"10.1172\/JCI79743","volume":"125","author":"J Albers","year":"2015","unstructured":"Albers J, Danzer C, Rechsteiner M, Lehmann H, Brandt LP, Hejhal T, Catalano A, Busenhart P, Goncalves AF, Brandt S et al (2015) A versatile modular vector system for rapid combinatorial mammalian genetics. 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