EWS/FLI1 is an oncogenic protein that is pathognomonic for Ewing sarcoma.[1] It is found in approximately 90% of all Ewing sarcoma tumors with the remaining 10% of fusions substituting one fusion partner with a closely related family member (e.g. ERG for FLI1).[2]

Origin

EWSR1 is a gene on chromosome 22 whose mRNA is translated into the protein Ewing sarcoma breakpoint region 1 (abbreviated EWS). The gene FLI1 resides on chromosome 11 where it encodes a member of the ETS transcription factor family, Friend leukemia integration 1 transcription factor (abbreviated FLI1).

Most fusions between EWS and FLI1 result from a t(11;22)(q24;q12) reciprocal chromosome translocation.[3] This translocation creates a chimeric transcript which fuses exons 1-7 of EWSR1 to exons 6-9 (or less commonly 5-9) of FLI1.[4][5]

It has recently been appreciated that almost half of EWS and FLI1 fusions are a result of chromoplexy.[6] Evidence of chromoplectic looping is enriched in both metastatic and p53 mutant tumors. Chromoplectic looping appears to be the mechanism involved in forming the EWS/ERG variant transcription factor. This preference is probably due to EWSR1 and ERG being in opposite orientations on the genome precluding the production of functional EWS/ERG via a reciprocal translocation.

Molecular Biology

EWS/FLI1 functions as both a pioneering transcription factor and potent oncogene.[7] Its expression leads to a complete restructuring of the transcriptome of the cell of origin to favor a tumorigenic state. EWS/FLI1 accomplishes this through a set of complementary mechanisms:

  1. The N-terminus of EWS/FLI1 retains the prion-like transactivation domain of EWSR1. This allows EWS/FLI1 to both bind RNA polymerase II and recruit the BAF complex. These interactions change heterochromatin to euchromatin at EWS/FLI1 DNA-binding sites effectively generating de novo enhancers.[8][9]
  2. The C-terminus of EWS/FLI1 retains the DNA-binding domain of FLI1. While wild-type FLI1 recognizes an ACCGGAAG core sequence,[10] EWS/FLI1 preferentially binds GGAA-repetitive regions. There is a positive correlation between the number of consecutive GGAA microsatellites, EWS/FLI1 binding, and target gene expression.[11]
  3. The core motif of ETS transcription factors includes a GGAA sequence. EWS/FLI1 may bind to such sequences with greater affinity than the wild-type ETS member disrupting the normal regulation of ETS target genes.[12]

References

  1. ↑ Grünewald, TGP (July 5, 2018). "Ewing sarcoma". Nature Reviews Disease Primers. 4 (5): 5. doi:10.1038/s41572-018-0003-x. PMID 29977059. S2CID 49571421.
  2. ↑ Tirode, Franck (May 1, 2015). "Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations". Cancer Discovery. 4 (11): 1342–1353. doi:10.1158/2159-8290.CD-14-0622. PMC 4264969. PMID 25223734.
  3. ↑ Downing, J. R. (November 1993). "Detection of the (11;22)(q24;q12) translocation of Ewing's sarcoma and peripheral neuroectodermal tumor by reverse transcription polymerase chain reaction". The American Journal of Pathology. 143 (5): 1294–1300. PMC 1887175. PMID 8238248.
  4. ↑ Zucman, Jessica (November 1992). "Cloning and characterization of the Ewing's sarcoma and peripheral neuroepithelioma t(11;22) translocation breakpoints". Genes, Chromosomes & Cancer. 5 (4): 271–277. doi:10.1002/gcc.2870050402. PMID 1283315. S2CID 23718350.
  5. ↑ Grohar, Patrick (January 26, 2016). "Functional genomic screening reveals splicing of the EWS-FLI1 fusion transcript as a vulnerability in Ewing sarcoma". Cell Reports. 14 (3): 598–610. doi:10.1016/j.celrep.2015.12.063. PMC 4755295. PMID 26776507.
  6. ↑ Anderson, Nathaniel D (February 28, 2019). "Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors". Science. 361 (6405): eaam8419. doi:10.1126/science.aam8419. PMC 6176908. PMID 30166462.
  7. ↑ Riggi, Nicolò Riggi (April 2008). "EWS-FLI-1 Expression Triggers a Ewing's Sarcoma Initiation Program in Primary Human Mesenchymal Stem Cells". Cancer Research. 68 (7): 2176–85. doi:10.1158/0008-5472.CAN-07-1761. PMID 18381423.
  8. ↑ Boulay, Gaylor (21 September 2017). "Cancer-Specific Retargeting of BAF Complexes by a Prion-like Domain". Cell. 171 (1): 163–178. doi:10.1016/j.cell.2017.07.036. PMC 6791823. PMID 28844694.
  9. ↑ Petermann, Robert (6 August 1998). "Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II". Oncogene. 17 (5): 603–610. doi:10.1038/sj.onc.1201964. PMID 9704926.
  10. ↑ Mao, Xiaohong (8 July 1998). "The FLI-1 and Chimeric EWS-FLI-1Oncoproteins Display Similar DNA Binding Specificities". The Journal of Biological Chemistry. 269 (27): 18216–18222. doi:10.1016/S0021-9258(17)32437-7. PMID 7517940.
  11. ↑ Johnson, Kirsten (November 1, 2017). "Identification of two types of GGAA-microsatellites and their roles in EWS/FLI binding and gene regulation in Ewing sarcoma". PLOS ONE. 12 (11): e0186275. Bibcode:2017PLoSO..1286275J. doi:10.1371/journal.pone.0186275. PMC 5665490. PMID 29091716.
  12. ↑ Riggi, Nicolò (October 30, 2014). "EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma". Cancer Cell. 26 (5): 668–681. doi:10.1016/j.ccell.2014.10.004. PMC 4492343. PMID 25453903.
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