ArticleGenome research2012
Tumor-specific retargeting of an oncogenic transcription factor chimera results in dysregulation of chromatin and transcription.
Article in Genome research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers.
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Who cites it
80 citing papers in PubMed, 116 citations in OpenAlex.
- Chromatin Immunoprecipitation Followed by Next-Generation Sequencing in Ewing Sarcoma.Methods in molecular biology (Clifton, N.J.) · 2027Article
- A Drosophila Study Model for EWS::FLI1-Induced Molecular Pathways.Methods in molecular biology (Clifton, N.J.) · 2027Article
- Ancient and animal-specific regulatory modes of EWS::FLI1 revealed by a minimal yeast model.PNAS nexus · 2026Article
- Fusion Oncoprotein EWSR1::FLI1 Invades Nucleosomes at Consensus ETS Motifs and GGAA Microsatellites.bioRxiv : the preprint server for biology · 2026Article
- EWSR1::FLI1 promotes neocentromere formation in ewing sarcoma cells.Cell reports · 2026Article
- Long-read analysis of tetrameric microsatellites with vmwhere supports GGAA repeat length-dependent chromatin state association in Ewing sarcoma.bioRxiv : the preprint server for biology · 2026Article
- Autocrine TGFβ2 enforces a transcriptionally hybrid cell state in Ewing sarcoma.Science advances · 2026Article
- KDM6 Demethylases Contribute to EWSR1::FLI1-Driven Oncogenic Reprogramming in Ewing Sarcoma.Cancer research · 2025Article
- Subversion of mRNA degradation pathways by EWSR1::FLI1 represents a therapeutic vulnerability in Ewing sarcoma.Nature communications · 2025Article
- Autocrine TGFβ2 enforces a transcriptionally hybrid cell state in Ewing sarcoma.bioRxiv : the preprint server for biology · 2025Article
- Article
- Human EWS-FLI protein levels and neomorphic functions show a complex, function-specific dose-response relationship inOpen biology · 2024Article
- Co-targeting JAK1/STAT6/GAS6/TAM signaling improves chemotherapy efficacy in Ewing sarcoma.Nature communications · 2024Article
- The Role of Phase-Separated Condensates in Fusion Oncoprotein-Driven Cancers.Annual review of cancer biology · 2023Article
- ETV6 dependency in Ewing sarcoma by antagonism of EWS-FLI1-mediated enhancer activation.Nature cell biology · 2023Article
- Regulation of EWSR1-FLI1 Function by Post-Transcriptional and Post-Translational Modifications.Cancers · 2023Review
- MS0621, a novel small-molecule modulator of Ewing sarcoma chromatin accessibility, interacts with an RNA-associated macromolecular complex and influences RNA splicing.Frontiers in oncology · 2023Article
- Systematic multi-omics cell line profiling uncovers principles of Ewing sarcoma fusion oncogene-mediated gene regulation.Cell reports · 2022Article
- EWS::FLI1 and HOXD13 Control Tumor Cell Plasticity in Ewing Sarcoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Article
- Neomorphic DNA-binding enables tumor-specific therapeutic gene expression in fusion-addicted childhood sarcoma.Molecular cancer · 2022Article
20 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Chromosomal translocations involving transcription factor genes have been identified in an increasingly wide range of cancers. Some translocations can create a protein "chimera" that is composed of parts from different proteins. How such chimeras cause cancer, and why they cause cancer in some cell types but not others, is not understood. One such chimera is EWS-FLI, the most frequently occurring translocation in Ewing Sarcoma, a malignant bone and soft tissue tumor of children and young adults. Using EWS-FLI and its parental transcription factor, FLI1, we created a unique experimental system to address questions regarding the genomic mechanisms by which chimeric transcription factors cause cancer. We found that in tumor cells, EWS-FLI targets regions of the genome distinct from FLI1, despite identical DNA-binding domains. In primary endothelial cells, however, EWS-FLI and FLI1 demonstrate similar targeting. To understand this mistargeting, we examined chromatin organization. Regions targeted by EWS-FLI are normally repressed and nucleosomal in primary endothelial cells. In tumor cells, however, bound regions are nucleosome depleted and harbor the chromatin signature of enhancers. We next demonstrated that through chimerism, EWS-FLI acquired the ability to alter chromatin. Expression of EWS-FLI results in nucleosome depletion at targeted sites, whereas silencing of EWS-FLI in tumor cells restored nucleosome occupancy. Thus, the EWS-FLI chimera acquired chromatin-altering activity, leading to mistargeting, chromatin disruption, and ultimately, transcriptional dysregulation.
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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 OpenQuestion graph.