GM-CSF has been shown to specifically stimulate proliferation of CD34+ hematopoietic progenitor cells. Although STAT3 is believed essential for transduction of GM-CSF-induced cell proliferation, the signaling mediated by STAT3 is not completely understood. Because survivin regulates cell proliferation and survival via its anti-apoptotic function, we studied the link between STAT3 signaling and survivin expression in CD34+ cells. Plasmids containing the survivin promoter sequence were constructed for luciferase reporter assays in CD34+ KG-1 cells stimulated with GM-CSF, and GM-CSF was found to stimulate survivin promoter activity. Chromatin immunoprecipitation (CHIP) and electrophoretic mobility shift assay (EMSA) further revealed that STAT3 binds to the core survivin promoter containing a STAT response element (SRE) TT(N)5AA at sites -264 to -256. Mutation or deletion of this SRE completely abolished effects of GM-CSF on survivin promoter activity. Furthermore, addition of specific JAK inhibitor and STAT3 siRNA were able to inhibit GM-CSF-induced survivin promoter activity and survivin expression. Inhibition of survivin by STAT3 siRNA or by withdrawal of GM-CSF in a GM-CSF-dependent CD34+ line TF-1 decreased cell growth and increased apoptosis. Our results suggest that survivin is a transcriptional target of STAT3, and that GM-CSF-stimulated CD34+ cell proliferation is regulated by the JAK/STAT3/survivin signaling pathway.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA