A De Novo Mouse Model of C11orf95-RELA Fusion-Driven Ependymoma Identifies Driver Functions in Addition to NF-kappa B

The majority of supratentorial ependymomas (ST-ependymomas) have few mutations but frequently display chromothripsis of chromosome 11q that generates a fusion between Cllorf95 and RELA (RELA(Fus)). Neural stem cells transduced with RELA Fus ex vivo form ependymomas when implanted in the brain. These tumors display enhanced NF-kappa B signaling, suggesting that this aberrant signal is the principal mechanism of oncogenesis. However, it is not known whether RELA Fus is sufficient to drive de novo ependymoma tumorigenesis in the brain and, if so, whether these tumors also arise from neural stem cells. We show that RELA(Fus) drives ST-ependymoma formation from periventricular neural stem cells in mice and that RELA(Fus)-induced tumorigenesis is likely dependent on a series of cell signaling pathways in addition to NF-kappa B.