GSE119971 ChIP-seq of A673 Ewing sarcoma cells using a specific anti-MYBL2 antibody

Contributors : Julian Musa ; Marie-Ming Aynaud ; Sandrine Grosset ête-Lalami ; Olivier Mirabeau ; Olivier Delattre ; Thomas G GrünewaldSeries Type : Genome binding/occupancy profiling by high throughput sequencingOrganism : Homo sapiensDeciphering principles of inter-individual tumor heterogeneity is essential for refinement of personalized anti-cancer therapy. Unlike cancers of adulthood, pediatric malignancies including Ewing sarcoma feature a striking paucity of somatic alterations except for pathognomonic driver-mutations that cannot explain overt variations in clinical outcome. Here we demonstrate in the Ewing sarcoma model how cooperation of a dominant oncogene and regulatory variants determine tumor growth, patient survival and drug response. We show that binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancer-like DNA element controls transcription of MYBL2, whose high expression promotes poor patient outcome via activation of pro-proliferative signatures. Genetic interference with this regulatory element almost abolished MYBL2 transcription, and MYBL2 knockdown decreased proliferation and tumorigenicity of Ewing sarcoma cells. Combined RNA- and ChIP-seq experiments identified CCNF, BIRC5 and AURKB as direct MYBL2 targets and critical mediators of its phenotype. In drug-response experiments high MYBL2 levels sensitized Ewing sarcoma cells for inhibition of its activating cyclin dependent kinase, CDK2, in vitro and in vivo, sugg...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Genome binding/occupancy profiling by high throughput sequencing Homo sapiens Source Type: research