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FB2026_01
,
released March 12, 2026
The Ewing sarcoma family of tumors (ESFT) involve translocations of the EWSR1 gene on chromosome 22 with various members of the ETS family of transcription factors; in most cases the FLI1 gene on chromosome 11 is the fusion partner of EWSR1. The protein encoded by EWSR1 includes an N-terminal transcriptional activation domain and a C-terminal RNA-binding domain; tumorigenic fusion proteins consist of the N-terminal transcriptional activation domain of EWSR1 and the C-terminal DNA-binding domain of a transcription factor protein.
In order to develop a Drosophila model of Ewing sarcoma, attempts were made to introduce UAS-driven fusions of human EWSR1-FLI (Hsap\EWSR1::Hsap\FLI1) into flies. In all initial experiments, no transformed animals were obtained. After multiple attempts, a single viable transformed animal was recovered. The transgene carried by this animal had undergone spontaneous mutation: a deletion of 17 nucleotides that causes the loss of six amino acids and a frameshift; in the resulting protein the 69 amino acid C-terminal tail of EWSR1-FLI that has been replaced by a new 64 amino acid sequence. The entire DNA binding domain of FLI1 remains. Surprisingly, deletion of the corresponding C-terminal sequences does not result in reduced toxicity. Based on tests in mouse and human cells, it appears that the modified frame-shifted fusion protein retains the neomorphic functions of the original EWSR1-FLI.
Using other fusions found in Ewing sarcoma, EWSR1-ERG (Hsap\ERG::Hsap\EWSR1) and EWSR1-FEV (Hsap\EWSR1::Hsap\FEV), similar results were obtained. The full-length and the corresponding C-terminal deletion versions of these fusion proteins appear to be as toxic as EWSR1-FLI; only the frameshift versions can be recovered as transgenes.
Although it was found that only low levels of expression allow survival to adulthood, recovery of animals carrying the modified EWSR1-FLI frame-shifted fusion protein has allowed development of a Drosophila model for Ewing sarcoma. Changes in the transcriptome have been assessed; interacting proteins have been identified.
[updated Mar. 2023 by FlyBase; FBrf0222196]
[EWING SARCOMA; ES](https://omim.org/entry/612219)
[EWS RNA-BINDING PROTEIN 1; EWSR1](https://omim.org/entry/133450)
Ewing sarcoma is a cancerous tumor that occurs in bones or soft tissues, such as cartilage or nerves. There are several types of Ewing sarcoma, including Ewing sarcoma of bone, extraosseous Ewing sarcoma, peripheral primitive neuroectodermal tumor (pPNET), and Askin tumor. [MedlinePlus, Ewing sarcoma; 2023.03.20]
The Ewing sarcoma family of tumors (primitive neuroectodermal tumors; PNET) comprise morphologically heterogeneous tumors that are characterized by nonrandom chromosomal translocations involving the EWSR1 gene on chromosome 22q12 and one of several members of the ETS family of transcription factors. The tumors include Ewing sarcoma, peripheral neuroepithelioma, and Askin tumor. [from MIM:612219; 2023.03.20]
Fusions of EWSR1 exon 7 to either FLI1 exon 6 (EWSR1-FLI1 type 1) or exon 5 (EWSR1-FLI1 type 2), account for 60% and 25% of EWSR1-FLI fusions, respectively (FBrf0255593 and references cited therein).
The Ewing sarcoma family of tumors (ESFT) involve translocations of the EWSR1 gene on chromosome 22q12 with various members of the ETS family of transcription factors. In approximately 90% of cases of ESFT, the FLI1 gene on chromosome 11 is the fusion partner of EWSR1; in approximately 10%, the EWSR1 fusion partner is the ERG gene on chromosome 22. [from MIM:612219; 2023.03.20]
The protein encoded by EWSR1 includes an N-terminal transcriptional activation domain and a C-terminal RNA-binding domain. Fusion proteins involving EWSR1 are produced by a number of different translocations implicated in tumorigenesis; such chimeric proteins usually consist of the N-terminal transcriptional activation domain of EWSR1 and the C-terminal DNA-binding domain of a transcription factor protein. [from Gene Cards, EWSR1; 2023.03.22]