Targeting DDX5 using FL118 suppresses mTOR signaling and tumorigenicity in JAK2V617F-driven myeloproliferative neoplasms.

The constitutively active mutant of the tyrosine kinase Janus kinase 2 (JAK2V617F) is a major driver of myeloproliferative neoplasms (MPNs). We previously demonstrated that JAK2V617F activates the transcription factor signal transducer and activator of transcription 5 (STAT5), which upregulates the expression of the RNA helicase DDX5. DDX5 promotes activation of the mTOR pathway and is essential for the proliferation and tumorigenicity of JAK2V617F-positive hematopoietic cell models, even though its RNA helicase activity is dispensable for JAK2V617F-induced transformation. In the present study, we investigated the therapeutic potential of targeting DDX5 using FL118, a camptothecin (CPT) derivative known to induce the proteasomal degradation of DDX5. In Ba/F3 cells expressing JAK2V617F and the erythropoietin receptor (EpoR), as well as in human erythroleukemia (HEL) cells harboring JAK2V617F, FL118, but not CPT, successfully induced DDX5 degradation. Consist with this, FL118, but not CPT, suppressed mTOR pathway activation and triggered apoptosis in both Ba/F3 cells expressing JAK2V617F and EpoR and HEL cells. In a subcutaneous tumor model, in which Ba/F3 cells expressing JAK2V617F and EpoR were transplanted into nude mice, oral administration of FL118 significantly reduced tumor growth and hepatosplenomegaly. Collectively, these findings establish DDX5 as a promising therapeutic target in MPNs and underscore the potential of FL118 as a treatment strategy for JAK2V617F-driven disease.