Phenotypic characterization with somatic genome editing and gene transfer reveals the diverse oncogenicity of ependymoma
- PDF / 7,855,303 Bytes
- 13 Pages / 595.276 x 790.866 pts Page_size
- 6 Downloads / 176 Views
Open Access
RESEARCH
Phenotypic characterization with somatic genome editing and gene transfer reveals the diverse oncogenicity of ependymoma fusion genes Mutsumi Takadera1,2, Kaishi Satomi3, Frank Szulzewsky4, Patrick J. Cimino4,5, Eric C. Holland4,6, Tetsuya Yamamoto2, Koichi Ichimura1* and Tatsuya Ozawa1*
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-celllike 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. Keywords: Supratentorial ependymoma, RELA, CRISPR/Cas9 system, Brain tumor mouse model, Gene rearrangement
Introduction Ependymomas are primary tumors of the central nervous system which occur throughout the craniospinal axis. These tumors occur in all age groups, but intracranial tumors are more common in children [16, 20]. The *Correspondence: [email protected]; [email protected] 1 Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5‑1‑1 Tsukiji, Chuo‑ku, Tokyo 104‑0045, Japan Full list of author information is available at the end of the article
current best available treatment for these patients is radical surgical removal, followed by local radiation therapy [18]. Since there is currently no effective chemotherapy for ependymomas, recurrent tumors may be lethal in some cases if not fully surgically resected [2, 9, 14]. Therefore, survival of ependymoma patients has not been drastically improved over the past decades [2], indicating that the development of a new treatment regimen is necessary for these intractable tumo
Data Loading...
