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Summary: The majority of supratentorial ependymomas (ST-ependymomas) have few mutations but frequently display chromothripsis of chromosome 11q that generates a fusion between C11orf95 and RELA (RELAFUS). Neural stem cells transduced with RELAFUS ex vivo form ependymomas when implanted in the brain. These tumors display enhanced NF-κB signaling, suggesting that this aberrant signal is the principal mechanism of oncogenesis. However, it is not known whether RELAFUS 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 RELAFUS drives ST-ependymoma formation from periventricular neural stem cells in mice and that RELAFUS-induced tumorigenesis is likely dependent on a series of cell signaling pathways in addition to NF-κB. : The C11orf95-RELA fusion (RELAFUS) has been found in a distinct subset of supratentorial ependymomas. Ozawa et al. show that RELAFUS is sufficient to drive ST-ependymoma formation from periventricular neural stem cells in mice. Furthermore, they show that RELAFUS-induced tumorigenesis might depend on other cell signaling pathways in addition to NF-κB. Keywords: ependymoma, fusion gene, NF-κB signaling, RCAS/tv-a system, mouse model, RELA, C11orf95