| Literature DB >> 33741710 |
Amir Arabzade1,2,3, Yanhua Zhao2,3, Srinidhi Varadharajan2,3, Hsiao-Chi Chen2,3,4, Selin Jessa5, Bryan Rivas2,3, Austin J Stuckert2,3, Minerva Solis2,3,4, Alisha Kardian2,3,4, Dana Tlais2,3, Brian J Golbourn6, Ann-Catherine J Stanton6, Yuen San Chan3,7,8,9, Calla Olson3,10,11, Kristen L Karlin3,10,11, Kathleen Kong3, Robert Kupp12,13, Baoli Hu6, Sarah G Injac2,3, Madeline Ngo1, Peter R Wang1, Luz A De León2, Felix Sahm14,15,16, Daisuke Kawauchi14,15,17, Stefan M Pfister14,18,19, Charles Y Lin3,10, H Courtney Hodges3,7,8,9, Irtisha Singh20, Thomas F Westbrook3,10,11, Murali M Chintagumpala2, Susan M Blaney2, Donald W Parsons2, Kristian W Pajtler14,18,19, Sameer Agnihotri6, Richard J Gilbertson12,13, Joanna Yi2,3, Nada Jabado5,21, Claudia L Kleinman5,21,22, Kelsey C Bertrand23,3, Benjamin Deneen24,25,26,27, Stephen C Mack23,3,4.
Abstract
More than 60% of supratentorial ependymomas harbor a ZFTA-RELA (ZRfus) gene fusion (formerly C11orf95-RELA). To study the biology of ZRfus, we developed an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE-driven ZRfus tumors by CUT&RUN, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZRfus-driven ependymoma. In addition to direct canonical NFκB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with PLAGL family transcription factor (TF) motifs. ZRfus activates gene expression programs through recruitment of transcriptional coactivators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by PLAGL TF proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks. SIGNIFICANCE: Ependymomas are aggressive brain tumors. Although drivers of supratentorial ependymoma (ZFTA- and YAP1-associated gene fusions) have been discovered, their functions remain unclear. Our study investigates the biology of ZFTA-RELA-driven ependymoma, specifically mechanisms of transcriptional deregulation and direct downstream gene networks that may be leveraged for potential therapeutic testing.This article is highlighted in the In This Issue feature, p. 2113. ©2021 American Association for Cancer Research.Entities:
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Year: 2021 PMID： 33741710 PMCID： PMC8418998 DOI： 10.1158/2159-8290.CD-20-1066
Source DB: PubMed Journal: Cancer Discov ISSN： 2159-8274 Impact factor: 39.397