STAT5 activation is required for interleukin-9-dependent growth and transformation of lymphoid cells

Interleukin-9 (IL-9) is a growth factor for T cells and various hematopoiet ic and lymphoid tumor cells. IL-9 signaling involves activation of Janus ki nase (JAK)1 and JAK3 kinases, and signal transducer and activator of transc ription (STAT)1, STAT3 and STAT5, Using a dominant negative form of STAT5 ( STAT5 Delta), we demonstrated that this factor is an important mediator of IL-9-dependent Ba/F3 cell growth, Mutation of the STAT binding site of the IL-9 receptor (tyr116phe) results in an important decrease in STAT activati on and inhibition of proliferation in the presence of IL-9. A small number of cells escape this Inhibition, and IL-9-dependent cell lines could be der ived. The selected cells required activation of STAT5 for growth, which was blocked by STAT5 Delta expression and enhanced by overexpression of wild-t ype STAT5. In contrast to parental cells, Ba/F3-Phe116 cells growing in the presence of IL-9 further progress to cytokine-independent tumorigenic clon es. These tumorigenic clones exhibited a strong cytokine-independent activa tion of JAK1 and STAT5, which most likely supports their proliferation. Tra nsfection of a constitutively activated variant of STAT5 promoted the growt h of wild-type Ba/F3 cells in the absence of cytokine. Finally, the express ion of the proto-oncogene pim-1 was correlated with STAT5 activation and ce ll growth. Our data suggest that STAT5 is an Important mediator of IL-9-dri ven proliferation and that dysregulation of STAT5 activation favors tumorig enesis of lymphoid cells.