EPEN-06. YAP1 SUBGROUP SUPRATENTORIAL EPENDYMOMA REQUIRES TEAD AND NUCLEAR FACTOR I-MEDIATED TRANSCRIPTIONAL PROGRAMS FOR TUMORIGENESIS

Ependymoma (EPN) is one of the most aggressive pediatric brain tumors, often arising in the supratentorial (ST) region. Our previous DNA methylation profling study has identified ST-EPN subgroups that are characterized by YAP1-related fusions through genomic structural rearrangements (hereafter called as ST-EPN-YAP1). No reports of amplification and hyper-activation of the YAP1 gene in ST-EPN-YAP1s postulate that YAP1-related fusions could have unique oncogenic function(s) in this type of cancer. Nevertheless, the lack of adequate models for ST-EPN-YAP1 had hindered the discovery of YAP1-fusion-specifc molecular mechanisms in EPN tumorigenesis and the development of effective targeted therapies for these tumors. Most recently, we developed a murine ST-EPN-YAP1 model by forced expression of YAP1-MAMLD1, the most dominant type of the fusion proteins in ST-EPN-YAP1 into cortical progenitors using in utero electroporation. Detailed histological analysis suggest that tumors arose from Pax6-positive neural stem cells, which is highly consistent with the highest expression of PAX6 in human ST-EPN-YAP1s across all EPN subgroups. MAMLD1-driven nuclear localization of the fusion protein is strongly associated with tumorigenesis. To investigate oncogenic functions of YAP1-MAMLD1, we performed a chIP-seq analysis on human ST-EPN-YAP1 primary tumors with an anti-YAP1 antibody. Intriguingly, ST-EPN-YAP1-specifc enhancers enriched for YAP1 peaks exhibited abundant transcriptional factor binding motifs of nuclear factor I and TEADs. Co-immunoprecipitation revealed that both TEAD and NFIA/B interact with YAP1-MAMLD1. Both the mutation of the TEAD binding site in the YAP1 fusion and dominant-negative inhibition of NFI proteins prevented tumor induction in mice. Collectively, we demonstrated that YAP1-MAMLD1 function as an oncogenic driver in ST-EPN-YAP1s through recruitment of TEAD and NFI transcriptional factors.