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.

中文翻译：

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体细胞基因组编辑和基因转移的表型表征揭示室管膜瘤融合基因的多种致癌性

复发性 RELA 和 YAP1 融合与幕上室管膜瘤的肿瘤发生密切相关。涉及 11q 的染色体碎裂和局灶拷贝数改变是这些肿瘤的标志。然而，尚不清楚染色体改变是否是导致融合转录的直接因果事件。此外，RELA 融合变体和 YAP1 融合的生物学意义尚未完全表征。在这项研究中，我们使用 CRISPR/Cas9 系统在 11q 上产生了基因重排，并研究了致癌室管膜瘤融合基因的形成。此外，我们在慢病毒基因转移模型中检查了 RELA 融合变体和 YAP1 融合的致癌潜力。我们观察到，培养细胞中 CRISPR/Cas9 介导的基因组重排成功诱导了内源性 RELA 融合事件。小鼠大脑中的体内基因组编辑导致了含有 Rela 融合基因的室管膜样脑肿瘤的发展。除了缺乏 Rel 同源结构域的变体外，所有测试的 RELA 融合变体都能够诱导肿瘤形成，尽管具有不同的功效。此外，YAP1-FAM118B 和 YAP1-MAMLD1 融合体的表达以不同的功效诱导梭形细胞样肿瘤的形成。我们的结果表明，涉及 Rela 基因座的染色体重排是在小鼠中形成 Rela 融合驱动的室管膜瘤的因果事件。此外，RELA 的类型。融合可能会影响肿瘤的侵袭性，并且 Rel 同源域对于 RELA 的致癌功能至关重要。融合。YAP1 融合基因在小鼠中表达时也具有致癌性。