Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA113399 | ENA |
REPOSITORIES: ENA
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Project description:Over-expression of the polycomb group gene BMI-1 is implicated in the pathogenesis of many human cancers. In this study, we investigate the role of BMI-1 as a functional oncogene in the Ewing’s Sarcoma Family of Tumors (ESFT), a highly aggressive group of bone and soft tissue tumors. Our data show that BMI-1 is highly expressed by the majority of primary ESFT and ESFT cell lines. However, in contrast to previous reports in other human cancer cell types, knockdown of BMI-1 in ESFT cell lines has no effect on cell survival. Instead, gain and loss of function studies in vitro and in vivo demonstrate that BMI-1 promotes the anchorage independent growth and tumorigenicity of ESFT. Importantly, we also find that modulation of BMI-1 alters the tumorigenicity of both p16-wild type and p16-null cell lines and that BMI-1-mediated effects on growth promotion are independent of CDKN2a repression. Gene expression profiling of ESFT cells following BMI-1 modulation reveals novel downstream effectors of BMI-1 function including key developmental, cell:cell and cell:matrix adhesion pathways. These data support a central role for BMI-1 in the pathogenesis of ESFT and reveal that p16-independent functions of BMI-1 are largely responsible for its oncogenic function in this tumor family. Keywords: Modification of BMI-1 expression in ESFT cell lines
2008-07-18 | GSE12064 | GEO
Project description:Ewing sarcoma is characterized by pathognomonic translocations fusing most frequently EWSR1 with FLI1 (EF1). In addition, Ewing sarcoma can also display alterations in STAG2, TP53 and CDKN2A (SPC). Starting from Ewing sarcoma derived human mesenchymal stem cells (MSCpat), we recapitulated this translocation and SPC alterations using a CRISPR/cas9 approach and generated a bona fide Ewing sarcoma model (EWIma1) displaying transcriptomic and epigenetic hallmarks of EwS.
2021-09-08 | GSE150777 | GEO
Project description:Ewing sarcoma is characterized by pathognomonic translocations fusing most frequently EWSR1 with FLI1 (EF1). In addition, Ewing sarcoma can also display alterations in STAG2, TP53 and CDKN2A (SPC). Starting from Ewing sarcoma derived human mesenchymal stem cells (MSCpat), we recapitulated this translocation and SPC alterations using a CRISPR/cas9 approach and generated a bona fide Ewing sarcoma model (EWIma1) displaying transcriptomic and epigenetic hallmarks of EwS.
2021-08-18 | GSE150776 | GEO
Project description:In this study, we characterize the fusion protein produced by the EPC1-PHF1 translocation in Low Grade Endometrial Stromal Sarcoma (LG-ESS) and Ossifying FibroMyxoid Tumors (OFMT). We express the fusion protein and necessary controls in K562 Cells. The fusion protein assembles a mega-complex harboring both NuA4/TIP60 and PRC2 subunits and enzymatic activities and leads to mislocalization of chromatin marks in the genome, linked to aberrant gene expression.
2020-12-03 | GSE162543 | GEO
Project description:Deciphering 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, suggesting MYBL2 as a predictive biomarker for targeted anti-CDK2-therapy.Collectively, our findings establish cooperation of somatic mutations and regulatory variants as a major determinant of tumor progression and indicate the importance of integrating the regulatory genome in the process of developing new diagnostic and/or therapeutic strategies to fully harness the potential of precision medicine.
2019-08-16 | GSE119971 | GEO