FLI1 – Ewing Sarcoma

Ewing sarcoma is defined by a somatic t(11;22)(q24;q12) chromosomal translocation that fuses the EWSR1 gene to the FLI1 transcription factor, generating the oncogenic EWS–FLI1 fusion protein. This fusion is detected in over 85% of Ewing sarcoma tumors and serves as a molecular hallmark for diagnosis and classification of the Ewing sarcoma family of tumors (ESFT) (PMID:10842247; PMID:16864960).

In clinical case series, EWS–FLI1 transcripts have been identified by RT‐PCR in primary tumors arising in typical (bone) and atypical (spinal nerve root) sites, confirming the diagnosis in diagnostically challenging locations (PMID:16864960). Fluorescence in situ hybridization (FISH) and RT‐PCR for EWS–FLI1 are now standard for definitive confirmation of Ewing sarcoma in biopsy specimens.

A germline variant study linked a regulatory polymorphism affecting EWSR1–FLI1–mediated gene activation to differential disease susceptibility, underscoring the relevance of FLI1 in both somatic oncogenesis and inherited risk modulation (PMID:26313223).

Biochemical characterization of the FLI1 protein revealed that it binds specific ETS‐consensus DNA sequences and functions as a transcriptional activator. Dysregulation via fusion to EWSR1 enhances aberrant transcriptional programs that drive oncogenesis in ESFT (PMID:8449942).

Mechanistic studies demonstrate that the EWS–FLI1 chimera interacts with and inhibits p53 transcriptional activity by binding to its N-terminal domain, impairing p21 and MDM2 induction and circumventing p53-dependent growth suppression in tumor cells (PMID:20153576).

Overall, there is strong clinical validity for the FLI1–Ewing sarcoma association: recurrent, disease‐defining somatic fusions in multiple cohorts, concordant functional assays in cellular models, and clinical utility for targeted diagnostic testing. Key take-home: detection of EWS–FLI1 is essential for accurate diagnosis and therapeutic stratification in Ewing sarcoma.

References

• Medical and pediatric oncology • 2000 • Biphenotypic sarcoma with characteristics of both a Ewing sarcoma and a desmoplastic small round cell tumor. PMID:10842247
• The Tohoku journal of experimental medicine • 2006 • Ewing's sarcoma in the spinal nerve root: a case report and review of the literature. PMID:16864960
• Nature Genetics • 2015 • Linking germline and somatic variation in Ewing sarcoma. PMID:26313223
• The Journal of Biological Chemistry • 1993 • Characterization of the ets oncogene family member, fli-1. PMID:8449942
• Cancer Letters • 2010 • Inhibition of the transcriptional function of p53 by EWS-Fli1 chimeric protein in Ewing Family Tumors. PMID:20153576

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