EPN-30YAP1-MAMLD1 FUSIONS ALONE ARE SUFFICIENT TO FORM SUPRATENTORIAL EPENDYMOMA-LIKE TUMORS IN MICE

EPN-30. YAP1-MAMLD1 FUSIONS ALONE ARE SUFFICIENT TO FORM SUPRATENTORIAL EPENDYMOMA-LIKE TUMORS IN MICE Kristian W. Pajtler1,2, Sebastian Brabetz1, Monika Mauermann1, Norman Mack1, Laura Sieber1, David T. W. Jones1, Hendrik Witt1,2, Huiqin Korkel-Qu3, Marc Zuckermann4, Jan Gronych4, Andrey Korshunov5,6, David Capper5,6, Hai-Kun Liu3, Stefan M. Pfister1,2, Marcel Kool1, and Daisuke Kawauchi1; German Cancer Research Center, Division of Pediatric Neurooncology, Heidelberg, Germany; University Hospital Heidelberg, Department of Pediatric Oncology, Hematology and Immunology, Heidelberg, Germany; German Cancer Research Center, Molecular Neurogenetics, Heidelberg, Germany; German Cancer Research Center, Molecular Genetics, Heidelberg, Germany; GermanCancer Research Center, Clinical Cooperation Unit Neuropathology, Heidelberg, Germany; University Hospital Heidelberg, Department of Neuropathology, Heidelberg, Germany Oncogenic fusions containing RELA orYAP1have recentlybeen identified as genetic hallmarks of distinct molecular subgroups of supratentorial ependymomas (ST-EPN), designated ST-EPN-RELA and ST-EPN-YAP1, respectively. ST-EPN-YAP1 tumors, exclusively found in pediatric patients, are molecularly andclinicallydifferentfromST-EPN-RELAtumors, suggesting that theyhave to be treated differently. YAP1 acts as a transcriptional regulator in the HIPPO tumor suppressor pathway. The lack of adequate models for ST-EPN-YAP1 has so far hindered efforts to develop effective targeted therapies for these tumors. In an attempt to model this subgroup, the most frequent fusion type, YAP1-MAMLD1, was constructed and cloned upstream of IRES-Luciferase into the pT2K transposable vector. The resulting vector was injected together with the Tol2 transposase into the lateral ventricle of E13.5 wildtype mouse embryos followed by transfection using an electroporation-based in vivo gene transferapproach.Afterbirth,YAP1-MAMLD1-expressing tumors,monitored using luciferase-based in vivo bioluminescence imaging, developed rapidly with 100% penetrance. The animals had to be sacrificed due to severe neurological symptoms on average at P20. Resulting tumors resembled molecular characteristics of their human counterparts. The YAP1-MAMLD1 protein was predominantly compartmentalized to the nuclei of tumor cells even when phosphorylated at serine residue 127, which normally retains YAP1 in the cytoplasm, implying constitutive activation of the YAP1 fusion protein. Conserved tumorigenic potential of transformed cells was confirmed by subsequent orthotopic transplantation of these tumor cells into immunocompromised recipient mice. We thus provide a novel model for ST-EPN-YAP1, which is currently entering first preclinical drug testings. Neuro-Oncology 18:iii30–iii39, 2016. doi:10.1093/neuonc/now070.29 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.