RERE and the Mediator complex cooperate with EWSR1::FLI1 in the reprogramming of Translation and Alternative Splicing, the latter being a therapeutically targetable vulnerability in Ewing sarcoma
The identification of the splicing factor RBM39 as a vulnerability in ES is supported by the extraordinary sensitivity of these tumors to monotherapy with RBM39 degrader indisulam, highlighting the potential of this approach as a novel and promising therapeutic strategy for Ewing sarcoma.
Ewing Sarcoma is defined by its hallmark mutation, a t(11;22)q24;q12) translocation which results in fusion of the EWSR1 and FLI1 genes. The fusion product, EWSR1::FLI1, contains the N-terminal low complexity domain (LCD) of EWSR1 and the DNA-binding Domain (DBD) of FLI1. EWSR1::FLI1 binds at microsatellites (µsats),...
Caleb J. Frye, R. Zhou, Lexis R. Rice et al.· Cancer Research· 0 citations
Ewing sarcoma is a rare and aggressive pediatric cancer caused by a translocation-derived fusion oncoprotein that fuses the N-terminal low complexity domain (LCD) of a FET protein (FUS, EWSR1, or TAF15) with the C-terminal portion of an ETS transcription factor from the ERG or PEA3 subfamilies. These fusion oncoprote...
Ruo-Wen Chen, R. Zhou, E. J. Tokarsky et al.· Cancer Research· 0 citations
Ewing sarcoma is an aggressive bone malignancy occurring in children, adolescents, and young adults. Most cases are caused by expression of the fusion oncoprotein EWSR1::FLI1, which contains the low complexity domain (LCD) of EWSR1 and the DNA-binding domain (DBD) of FLI1. Previous genomic studies indicate EWSR1::FLI1...
Ruo-Wen Chen, R. Zhou, E. J. Tokarsky et al.· bioRxiv· 0 citations
Abstract Over 90% of Ewing sarcomas (EWS) are driven by the EWS–FLI1 fusion oncoprotein. EWS–FLI1 acts as a pioneer transcription factor, altering the expression of hundreds of genes including many long non-coding RNAs (lncRNAs). The role of these lncRNAs in the oncogenesis of EWS is mostly unknown. We developed a CRIS...
Marcela Briones-Martin-Del-Campo, Alex G. Lee, Truc Dinh et al.· NAR Cancer· 0 citations
Despite the revolutionary impact of genome engineering tools in medicine, the safe and effective intracellular delivery of CRISPR remains a major obstacle for clinical applications. Here, we utilize precision molecular targeting and delivery strategies based on CRISPR/dCas9 systems adapted for epigenetic repression (dC...
Shahama Taifour, Chee-Wai Wong, Christopher P. Wallis et al.· Molecular Therapy· 0 citations
The conversion of transcriptionally silent GGAA microsatellites (GGAAµSats) into functional enhancers by FET::ETS oncogenic fusions is a hallmark of Ewing sarcoma. However, emerging evidence implicates non-fused, full-length oncogenic ETS transcription factors in activating these repeats in other malignancies. Evaluati...
Cristina Molnar, Jose Reina, J. Mora et al.· G3· 0 citations
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