Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite

@article{Grnewald2015ChimericER,
  title={Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite},
  author={Thomas G. P. Gr{\"u}newald and Virginie Bernard and Pascale Gilardi-Hebenstreit and Virginie Raynal and Didier Surdez and Marie-Ming Aynaud and O Mirabeau and Florencia Cidre-Aranaz and Franck Tirode and Sakina Zaidi and Ga{\"e}lle P{\'e}rot and Anneliene H. Jonker and Carlo Lucchesi and Marie-C{\'e}cile Le Deley and Odile Oberlin and Perrine Marec-Berard and Am{\'e}lie S. V{\'e}ron and St{\'e}phanie Reynaud and Eve Lapouble and Valentina Boeva and Thomas Rio Frio and Javier Alonso and Smita Bhatia and Gaelle Pierron and G{\'e}raldine Cancel-Tassin and Olivier Cussenot and David G. Cox and Lindsay M. Morton and Mitchell J. Machiela and Stephen J. Chanock and Patrick Charnay and Olivier Delattre},
  journal={Nature Genetics},
  year={2015},
  volume={47},
  pages={1073-1078}
}
Deciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs. A recent genome-wide association study identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and… 
Targeting the CALCB/RAMP1 axis inhibits growth of Ewing sarcoma
TLDR
The findings suggest that CALCB is a direct EWSR1-FLI1 target and that targeting the CALCB/RAMP1 axis may offer a new therapeutic strategy for inhibition of EwS growth.
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
It is discovered that SOX6 interferes with the antioxidant system resulting in constitutively elevated reactive oxygen species (ROS) levels that create a therapeutic vulnerability toward the ROS-inducing drug Elesclomol.
Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility
TLDR
The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk, and three new EWS risk loci that reside near GGAA repeat sequences, are reported.
Systems Biology Analysis for Ewing Sarcoma.
TLDR
It is concluded that despite the seeming simplicity of the oncogene action of EwS, a lot has yet to be understood on the systems-wide mechanisms connecting the driver mutation and the major cellular phenotypes of this pediatric cancer.
Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma
TLDR
The authors show that EWSR1-FLI1 increases the activity of the developmental transcription factor SOX6, which promotes tumor growth but also increases sensitivity to oxidative stress.
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References

SHOWING 1-10 OF 63 REFERENCES
The Oncogenic EWS-FLI1 Protein Binds In Vivo GGAA Microsatellite Sequences with Potential Transcriptional Activation Function
TLDR
Using a ChIP-Seq approach to investigate EWS-FLI1-bound DNA sequences in two Ewing cell lines, it is shown that this chimeric transcription factor preferentially binds two types of sequences including consensus ETS motifs and microsatellite sequences.
Microsatellites as EWS/FLI response elements in Ewing's sarcoma
TLDR
It is found that EWS/FLI uses GGAA microsatellites to regulate the expression of some of its target genes including NR0B1, a gene required for Ewing's sarcoma oncogenesis and an unprecedented route to specificity for ETS proteins and use of microsatelliteites in tumorigenesis.
Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations.
TLDR
Tumors that harbor STAG2 and TP53 mutations have a particularly dismal prognosis with current treatments and require alternative therapies, and novel drugs that target epigenetic regulators may constitute viable therapeutic strategies in a subset of patients with mutations in chromatin modifiers.
Targeting the EWSR1-FLI1 oncogene-induced protein kinase PKC-β abolishes ewing sarcoma growth.
TLDR
It is found that transcriptional activation of PRKCB was directly regulated by the chimeric fusion oncogene EWSR1-FLI1 that drives this cancer.
Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma
TLDR
Variants at candidate risk loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2, and the major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence.
The genomic landscape of pediatric Ewing sarcoma.
TLDR
Next-generation sequencing of Ewing sarcoma found remarkably few mutations, however, it was discovered that loss of STAG2 expression occurs in 15% of tumors and is associated with metastatic disease, suggesting a potential genetic vulnerability in Ewing Sarcoma.
Tumor-specific retargeting of an oncogenic transcription factor chimera results in dysregulation of chromatin and transcription.
TLDR
It is found that in tumor cells, EWS-FLI targets regions of the genome distinct from FLI1, despite identical DNA-binding domains, which leads to mistargeting, chromatin disruption, and ultimately, transcriptional dysregulation.
The Genomic Landscape of the Ewing Sarcoma Family of Tumors Reveals Recurrent STAG2 Mutation
TLDR
The largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines) is reported, finding that EFT has a very low mutational burden but frequent deleterious mutations in the cohesin complex subunit STAG2 and that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and these tumors do not have a characteristic Ewing sarcoma gene expression signature.
EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma.
TLDR
Divergent chromatin-remodeling patterns repress tumor suppressors and mesenchymal lineage regulators while activating oncogenes and potential therapeutic targets, such as the kinase VRK1.
Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours
TLDR
Phylogenetically conserved restriction fragments in the vicinity of EWSR1 and EWSR2, the genomic regions where the breakpoints of chromosome 22 and chromosome 11 are, respectively, have allowed identification of transcribed sequences from these regions and has indicated that a hybrid transcript might be generated by the translocation.
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