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Regulation Of The Inhibitor-of-apoptosis Family Member Survivin In Normal Cord Blood And Bone Marrow CD34+ Cells By Hematopoietic Growth Factors: Implication Of Survivin Expression In Normal Hematopoiesis

Seiji Fukuda, Louis M. Pelus

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The inhibitor-of-apoptosis protein survivin is expressed in most cancers and leukemias and during fetal development, but not in most normal adult tissues. Survivin expression was analyzed in umbilical cord blood (UCB) and adult bone marrow CD34+cells and in the factor-dependent MO7e cell line; also investigated was whether survivin expression was regulated by hematopoietic growth factors. Survivin messsenger RNA (mRNA) and protein were expressed in fresh UCB and marrow CD34+ cells. The combination of thrombopoietin, Flt3 ligand, and stem cell factor upregulated survivin expression in CD34+ cells within 24 hours; survivin expression was cell-cycle related and highest during G2/M, whereas growth-factor withdrawal resulted in decreased survivin expression. Cell-cycle fractionation of UCB CD34+ with Hoechst-33342/pyronin-Y demonstrated that survivin message was undetectable in freshly isolated G0 cells, but present in G1 cells. After cytokine stimulation, survivin mRNA and protein expression were observed in both G0 and G1 CD34+ cells as well as in cells that had progressed to S and G2/M phase, indicating that survivin expression is regulated in all phases of the cell cycle. This contrasts with the expression of survivin predominantly during G2/M in cancer cells. In CD34+ cells and MO7e cells, growth factor–mediated upregulation of survivin was associated with inhibition of apoptosis, and downregulation of survivin was coincident with increased apoptosis. Furthermore, an inverse correlation between survivin and active caspase-3 was observed in CD34+ cells. These findings demonstrate that survivin is not a cancer-specific antiapoptotic protein and plays a regulatory role in normal adult hematopoiesis.