(P 343) TLE1 DISRUPTION DOES NOT IMPEDE SYNOVIAL SARCOMAGENESIS

Objective: Synovial sarcoma (SyS) is characterized by the SS18::SSX fusion oncoprotein, originating from a chromosomal translocation between chromosomes 18 and X. It has been reported that SS18::SSX oncoprotein interacts with transcription factors ATF2 and TLE1 to form a core complex, repressing ATF2 target genes, which transcriptional repression leads to tumor formation. Building upon the previous finding, the objective of this study is to investigate the effect of TLE1 disruption on synovial sarcomagenesis using an engineered mouse model.

Methods: To explore the role of TLE1 in SyS progression and its interaction with the SS18::SSX fusion protein, we developed genetically engineered mouse models with Tle1 conditional knockout. We utilized quantitative PCR (RT-qPCR) to assess Tle1 expression levels in resultant tumors. Histological examinations were conducted to observe morphological changes, and tumor growth experiments were performed to evaluate the impact on tumorigenesis. Additionally, epigenomics explored the interaction between the Tle1 locus and the SS18::SSX fusion oncoprotein.

Results: Tumor growth assays indicated that TLE1 disruption does not influence tumor growth rates in SyS. Histological evaluation showed no significant changes in tumor morphology associated with TLE1 disruption. RT-qPCR effectively confirmed the reduction of Tle1 expression in the experimental models, but no compensating overexpression of other TLE-family paralogs. It also confirmed that none of the purportedly repressed genes were derepressed by TLE1 disruption. Chromatin binding assays identified the Tle1 locus as a direct target of SS18::SSX binding and enhancer loops in mouse and human SyS.

Conclusion: These results suggest that TLE1, while a robust diagnostic marker for SyS due to its consistent expression and molecular interaction with the oncoprotein, acts more as a passenger rather than a driver of the SyS pathogenesis. This distinction underscores TLE1’s significant utility in the diagnosis of SyS, reconfirming its value for early detection and monitoring, but diminishing interest in therapeutic targeting of TLE1 as a likely dependency in this disease.