期刊
CANCER DISCOVERY
卷 11, 期 9, 页码 2200-2215出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-20-1066
关键词
-
类别
资金
- V Foundation Scholar in Cancer Research Award
- Cancer Prevention Research Institute of Texas (CPRIT) scholar award [RR170023]
- Alex's Lemonade Stand Foundation (ALSF) A award
- THINC Seed Grant
- NIH-National Institute of Neurological Disease and Stroke [R01NS116361]
- Hyundai Hope on Wheels
- St. Baldrick's Foundation Early Career Development Award
- THINC Seed Grant, K12 award [5K12CA090433-17]
- Alex's Lemonade Stand Foundation Center of Excellence Developmental Therapeutic Scholar Award
- Canadian Institutes of Health Research (CIHR) [PJT-156086]
- National Cancer InstituteCancer Therapeutic Discovery [U01-CA217842]
- Cancer Prevention Research Institute of Texas [RP150334]
- CPRIT [RR170036]
- NCI [R00CA187565]
- NIGMS [R35GM137996]
- Rally Foundation
- NSERC [RGPIN-2016-04911]
The study reveals the critical role of ZR(fus) in supratentorial ependymomas by activating the NF kappa B pathway and recruiting transcriptional coactivators to promote gene expression. Its target genes are often involved in developmental programs and tumor networks, providing insights for potential therapeutic strategies.
More than 60% of supratentorial ependymomas harbor a ZFTA-RELA (ZR(fus)) 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 ZR(fus) tumors by CUT& RUN, chromatin immunoprecipitation sequencing, assay for transposaseaccessible chromatin sequencing, and RNA sequencing and compared with human ZR(fus)-driven ependymoma. In addition to direct canonical NF kappa B pathway activation, ZR(fus) 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. ZR(fus) activates gene expression programs through recruitment of transcriptional coactivators (BRD4, EP300, CBP, Pol2) that are amenable to pharmacologic inhibition. Downstream ZR(fus) 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据