Functional Genomic Screening Reveals Splicing of the EWS-FLI1 Fusion Transcript as a Vulnerability in Ewing Sarcoma

Cell Reports
Patrick J GroharNatasha J Caplen

Abstract

Ewing sarcoma cells depend on the EWS-FLI1 fusion transcription factor for cell survival. Using an assay of EWS-FLI1 activity and genome-wide RNAi screening, we have identified proteins required for the processing of the EWS-FLI1 pre-mRNA. We show that Ewing sarcoma cells harboring a genomic breakpoint that retains exon 8 of EWSR1 require the RNA-binding protein HNRNPH1 to express in-frame EWS-FLI1. We also demonstrate the sensitivity of EWS-FLI1 fusion transcripts to the loss of function of the U2 snRNP component, SF3B1. Disrupted splicing of the EWS-FLI1 transcript alters EWS-FLI1 protein expression and EWS-FLI1-driven expression. Our results show that the processing of the EWS-FLI1 fusion RNA is a potentially targetable vulnerability in Ewing sarcoma cells.

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Citations

Jan 25, 2018·Oncogenesis·Yanfeng LiTaosheng Chen
Aug 14, 2019·Wiley Interdisciplinary Reviews. RNA·Carla NecklesNatasha J Caplen
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Oct 17, 2018·Journal of Clinical Medicine·Yu-Dong CaiXiangyin Kong
Oct 13, 2020·Molecular Carcinogenesis·Soumya Sundara RajanNatasha J Caplen
Oct 10, 2020·Nature Communications·M Martinez-LageS Rodriguez-Perales
Feb 1, 2021·Cancer Letters·Ignacio Campillo-MarcosPedro A Lazo
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Mar 20, 2020·ACS Chemical Biology·Robert E BoerJohn S Schneekloth
Aug 24, 2021·The Journal of Pediatric Pharmacology and Therapeutics : JPPT : the Official Journal of PPAG·Sara D A AngioneClinton F Stewart

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