Stat5 Is Essential for BCR-ABL-Transformed Chronic Myeloid Leukemia (CML) Associated with Increased CCN3 Gene Expression.

Signal transducers and activators of transcription5 (Stat5) proteins are involved in many cellular processes through mediated cytokine, hormone, and growth factor signaling. But its role in disease pathogenesis has not been fully elucidated. Recently, activation of BCR-ABL has been reported to regulate a novel gene, CCN3 in cell lines and primary cells derived from chronic myeloid leukemia (CML) patients. To investigate the function of Stat5 in CML initiation and maintenance and determine the downstream target genes on Jak-Stat5 pathway, we developed a BCR-ABL - induced CML - like disease model by using retro-viral infection in Cre-mediated Stat5 knockout transgenic mice and analyzed the progress of CML. We also used Stat5 knockout (Stat5 KO) mice to perform gene profiling. Results: Our study showed that loss of Stat5 resulted in increased survival rate and remission of CML. Microarray analysis showed that CCN3 expression was down-regulated in KL cells derived from Stat5 KO mice. BCR-ABL-activated Stat5 increased expression level of CCN3 in CML cells. We further determined that Stat5 binds to CCN3 promoter region in IL-3 stimulated 32D cells and BCR-ABL-induced CML cells. Conclusions: Our study suggested that Stat5 is essential for BCR-ABL transformed CML and that CCN3 is involved in normal hematopoiesis and CML development. Further study will be necessary to uncover the function of CCN3 and more targets of Stat5 pathway in CML development and discover the therapeutic significance.

No relevant conflicts of interest to declare.