PDTM-45. MECHANISM OF NEURAL STEM CELL TRANSFORMATION BY C11ORF95-RELA TRANSLOCATIONS

Abstract:: Abstract Highly recurrent chromosome translocations that produce oncogenic fusions are a prime example of practical therapeutic targets translating into clinical successes. We have previously described the genetic driver of supratentorial ependymomas as translocation fusions of the C11orf95 gene of unknown function and RELA, the canonical nuclear transducer of NF-κB signaling5. Subsequent studies have reinforced our original findings on the frequency (>70%) of these C11orf95-RELA (CR) fusions in human disease, as well as their transformative potential in murine models. However, the mechanisms by which CR fusions transform neural stem cells into ependymomas remain elusive. Using a multi-OMICS approach, we show that oncogenic C11orf95 fusions co-opt spatio-temporally regulated transcriptional activators in ependymoma. We henceforth demonstrate that supratentorial ependymomas, which have been previously described as a RELA fusion disease6, are truly a C11orf95 fusion disease, with C2H2-ZFs serving as a scaffold for transcriptional dysregulation. Our studies lay the architectural framework for a molecular roadmap into the heart of C11orf95 fusion ependymomas, elucidating the biochemical mechanisms which furnish the capacity of these fusions to operate as single gene oncogenes, and henceforth providing potential avenues for therapeutic intervention in ependymoma.

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