ReviewPromiscuous partnerships in Ewing's sarcoma
Section snippets
The EWS/FLI fusion in Ewing’s sarcoma
Karyotypically, Ewing’s sarcoma is a relatively simple neoplasm, harboring the main cytogenetic hallmark t(11;22)(q24;q12) translocation 9, 18. Approximately 85% of Ewing’s sarcoma tumors harbor this characteristic translocation. The t(11;22) rearrangement creates a fusion between the Ewing’s sarcoma breakpoint region 1 gene (EWSR1) on chromosome 22 and the Friend leukemia virus integration site 1 gene (FLI1) on chromosome 11 (19) (Figure 1A).
The EWSR1 gene encodes the EWS protein, which is a
EWS/FLI fusion subtypes
“EWS/FLI” is not a single molecular entity, but rather includes a set of highly related isoforms or subtypes. This diversity is a result of differences in genomic breakpoints in the EWSR1 and FLI1 genes. Breakpoints have been observed in a variety of introns in these genes 66, 67, 68. In each case, the resultant fusion is really in the introns of the genes, and through typical splicing processes of the transcribed RNA, fusion mRNAs are generated containing 5′ exons derived from EWSR1 fused to
Other EWS/ETS fusions in Ewing’s sarcoma
The ETS family of proteins is comprised of transcription factors that are characterized by the presence of a highly conserved 85 amino acid ETS domain that mediates sequence-specific DNA binding (27). In many cases, ETS proteins function as signal-dependent transcriptional regulators controlling cellular differentiation and proliferation 74, 75. Many different members of the ETS family have been shown to be involved in oncogenesis, predominantly, by chromosomal translocations that fuse ETS
TET/ETS fusions in Ewing’s sarcoma
To further add to the complexity of Ewing’s sarcoma, non-EWS fusions have been identified in rare cases of the disease. As discussed above, EWS is a member of the TET (TLS/EWS/TAF15) family of proteins. Gene fusions have been identified between the TET family member TLS (also called FUS) and two different ETS family members, ERG and FEV (Figure 2). TLS/ERG and TLS/FEV fusion proteins are found in <1% of Ewing’s sarcoma cases. Conceptually, again, these “TLS/ETS” fusions are likely to
EWS/NFATc2
In 2009 there was a report on the identification of a new translocation partner of the EWSR1 gene, NFATc2 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 also known as NFAT1 or NFATp), in “Ewing’s-like tumors” (94). In all cases identified, an in-frame chimeric fusion between exon 8 of EWSR1 and exon 3 of the NFATc2 gene was identified (Figure 3). The EWS/NFATc2 fusion harboring solid tumors were diagnosed in four male patients who were 16, 21, 25 and 39 years of age.
Cell-of-origin and cellular context in Ewing’s sarcoma
One important aspect that is crucial to understanding the biology of Ewing’s sarcoma is the identification and characterization of the cell-of-origin for the disease. Currently there is no resolution to this issue. On the one hand, there is a growing body of work suggestive of a mesenchymal stem or progenitor cell as the precursor cell type for Ewing’s sarcoma 118, 119, 120, 121, 122. On the other hand, several observations are consistent with a neural crest cell-of-origin 123, 124, 125.
Potential mechanisms of chromosomal translocations in Ewing’s sarcoma
There is relatively little known about the mechanism of generation of TET/ETS (and non-TET/ETS) chromosomal translocations in Ewing’s and Ewing’s-like tumors, but a few hypotheses have been advanced since the discovery of EWS/FLI nearly 20 years ago. Homologous recombination at site-specific sequences has been suggested as the potential mechanism of chromosomal translocations in human hematological malignancies such as lymphoid neoplasms (139). In contrast, analysis of 113 interchromosomal
Is it time to revisit the concept that TET/ETS fusions are pathognomonic for Ewing’s sarcoma?
The initial discovery of EWS/FLI and the demonstration that this fusion functions as an aberrant transcription factor to mediate oncogenesis in Ewing’s sarcoma provided a simple model for Ewing’s sarcoma tumorigenesis: EWS/FLI sits at the top of a transcriptional hierarchy to dysregulate a set of target genes that together mediate tumor formation. The discovery of the EWS/ERG fusion, with its highly conserved domain structure to EWS/FLI, provided additional support for this hypothesis. Indeed,
Should we care if non-TET/ETS-containing tumors are Ewing’s sarcoma?
Ewing’s sarcoma itself is a rare tumor, with approximately 250 new cases occurring in the United States each year (145). If each of the rare TET/ETS and non-TET/ETS fusion variants occurs in 1% of cases or less, these will contribute to a very small portion, and a very small total number of tumors. Are these an important set of tumors to understand?
We would suggest that these are indeed important tumors to understand. In the first place, patients will develop tumors harboring these rare fusion
Summary and conclusions
Ewing’s sarcoma is an enigmatic cancer driven by chromosomal translocation derived fusion oncogenes. TET/ETS proteins are undoubtedly the central mediators in the pathogenesis of Ewing’s sarcoma. In particular EWS/FLI, the most common gene rearrangement in Ewing’s sarcoma, is widely used as a molecular diagnostic marker for the disease. However, recent identification of an increasing number of similar TET/ETS as well as non-TET/ETS rearrangements has further complicated molecular diagnostics
Acknowledgments
S.S. is a University of Utah Howard Hughes Medical Institute Med into Grad Program Scholar. S.L.L. is supported by the NIH (R21 CA138295, R01 CA140394), the Terri Anna Perine Sarcoma Fund, the University of Utah Department of Pediatrics and Huntsman Cancer Institute/Huntsman Cancer Foundation. S.L.L. also acknowledges support to the Huntsman Cancer Institute (grant P30 CA042014). We would like to thank our reviewers for suggesting changes that allowed for a more comprehensive review of the
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2022, Biochemical PharmacologyCitation Excerpt :Upon chromosomal translocation, the ETS binding domain of FLI1 undergoes a conformational change which allows activation of a wider repertoire of genes with respect to the wt protein [34–36]. Through the aberrant conjugation of partners’ activities and neomorphic functions, EWS-FLI1 oncoproteins heavily impact transcription and splicing mechanisms causing a massive rewiring of the transcriptome and a widespread reprogramming of the epigenome [7,21,28,36–38]. By binding DNA at either ETS-like sequences that contain GGAA motif or at GGAA microsatellites, the oncoproteins act as potent transcriptional activators [39].