Distinct RET Fusion Partner Genes in RET-Rearranged Spindle Cell Tumors Contribute to Varied Transformation Capacities

RET -rearranged spindle cell tumors represent a group of soft tissue tumors with heterogeneous clinical presentations. While some tumors are benign, others display malignant behavior with metastatic potential. The underlying causes of this heterogeneity are unknown but are suspected to be associated with the diverse fusion partner genes involved in RET rearrangements. We describe a unique case of a spindle cell tumor with an MYH10::RET fusion that originated in the knee and metastasized to the lung. The tumor initially responded to anti- RET therapy but subsequently relapsed due to a new NTRK1 fusion. The disease has since been effectively managed with a third-generation inhibitor targeting both RET and NTRKs. This supports our hypothesis that MYH10 as a fusion partner contributes to the tumor's aggressive clinical course. We established cell lines stably expressing MYH10::RET and CCDC6::RET , and we found that MYH10::RET -expressing cells demonstrated significantly more aggressive phenotypes as compared to cells expressing CCDC6::RET . Further analysis revealed that MYH10::RET possesses more potent kinase activity than CCDC6::RET , providing a mechanistic explanation for the observed differences in tumor behavior. We conclude that distinct RET fusion partners significantly contribute to the clinical heterogeneity in RET -rearranged spindle cell tumors.