ArticleProceedings of the National Academy of Sciences of the United States of America2015
Oncogenic fusion protein EWS-FLI1 is a network hub that regulates alternative splicing.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 109 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
109 citing papers in PubMed, 144 citations in OpenAlex.
- Open-Label, Multicenter, Phase I/II, First-in-Human Trial of TK216: A First-Generation EWS::FLI1 Fusion Protein Antagonist in Ewing Sarcoma.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2024Trial
- IL1RAP Antibody-Drug Conjugates Potently Target Primary and Metastatic Diseases in Multiple Oncofusion-Driven Cancers.Cancer discovery · 2026Article
- Disruption of microhomology-mediated end joining in Ewing sarcoma.Molecular cell · 2026Article
- The dynamic and heterogeneous composition of biomolecular condensates and its functional relevance.Nature reviews. Molecular cell biology · 2026Review
- Dynamic regulation of endogenous transcription factor hubs at single-molecule resolution.bioRxiv : the preprint server for biology · 2026Article
- Deregulated enhancer-promoter communication in cancer through altered nuclear architecture.International journal of cancer · 2026Review
- A de novo assembly based fusion gene detection concept based on DNA-seq data of 100 Ewing sarcoma cases.Briefings in bioinformatics · 2026Article
- A Novel FLI1 Monoclonal Antibody Which Recognizes EWS::FLI1 with High Affinity Is Useful for Detecting Ewing Sarcoma.Antibodies (Basel, Switzerland) · 2025Article
- EWS::FLI1-DHX9 interaction promotes Ewing sarcoma sensitivity to DNA topoisomerase 1 poisons by altering R-loop metabolism.Oncogene · 2025Article
- Disruption of Microhomology-mediated End-joining in Ewing Sarcoma.bioRxiv : the preprint server for biology · 2025Article
- Biomolecular Condensates as Emerging Biomaterials: Functional Mechanisms and Advances in Computational and Experimental Approaches.Advanced materials (Deerfield Beach, Fla.) · 2025Review
- The Spliceosomal Peptidyl Prolyl Isomerase Like 1 Interacts with the Low-Complexity Domain of the RNA Binding Protein EWS Modulating Its Phase Separation Behavior.Biochemistry · 2025Article
- Design of intrinsically disordered region binding proteins.Science (New York, N.Y.) · 2025Article
- Subversion of mRNA degradation pathways by EWSR1::FLI1 represents a therapeutic vulnerability in Ewing sarcoma.Nature communications · 2025Article
- Apoptosis-inducing factor (AIF) at the crossroad of cell survival and cell death: implications for cancer and mitochondrial diseases.Cell communication and signaling : CCS · 2025Review
- Drug resistance and tumor heterogeneity: cells and ensembles.Biophysical reviews · 2025Review
- Phase separation of the oncogenic fusion protein EWS::FLI1 is modulated by its DNA-binding domain.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Clinical characterization and therapeutic targeting of fusion genes in oncology.Future oncology (London, England) · 2025Review
- DHX9 helicase impacts on splicing decisions by modulating U2 snRNP recruitment in Ewing sarcoma cells.Nucleic acids research · 2025Article
- Bioinformatics analysis combined with untargeted metabolomics reveals lipid metabolism-related genes and their biological markers in chronic spontaneous urticaria.Frontiers in genetics · 2025Article
49 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
Abstract
The synthesis and processing of mRNA, from transcription to translation initiation, often requires splicing of intragenic material. The final mRNA composition varies based on proteins that modulate splice site selection. EWS-FLI1 is an Ewing sarcoma (ES) oncoprotein with an interactome that we demonstrate to have multiple partners in spliceosomal complexes. We evaluate the effect of EWS-FLI1 on posttranscriptional gene regulation using both exon array and RNA-seq. Genes that potentially regulate oncogenesis, including CLK1, CASP3, PPFIBP1, and TERT, validate as alternatively spliced by EWS-FLI1. In a CLIP-seq experiment, we find that EWS-FLI1 RNA-binding motifs most frequently occur adjacent to intron-exon boundaries. EWS-FLI1 also alters splicing by directly binding to known splicing factors including DDX5, hnRNP K, and PRPF6. Reduction of EWS-FLI1 produces an isoform of γ-TERT that has increased telomerase activity compared with wild-type (WT) TERT. The small molecule YK-4-279 is an inhibitor of EWS-FLI1 oncogenic function that disrupts specific protein interactions, including helicases DDX5 and RNA helicase A (RHA) that alters RNA-splicing ratios. As such, YK-4-279 validates the splicing mechanism of EWS-FLI1, showing alternatively spliced gene patterns that significantly overlap with EWS-FLI1 reduction and WT human mesenchymal stem cells (hMSC). Exon array analysis of 75 ES patient samples shows similar isoform expression patterns to cell line models expressing EWS-FLI1, supporting the clinical relevance of our findings. These experiments establish systemic alternative splicing as an oncogenic process modulated by EWS-FLI1. EWS-FLI1 modulation of mRNA splicing may provide insight into the contribution of splicing toward oncogenesis, and, reciprocally, EWS-FLI1 interactions with splicing proteins may inform the splicing code.
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What Socratic holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.