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Blood, 1 October 2001, Vol. 98, No. 7, pp. 2091-2100
HEMATOPOIESIS
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 and
Louis M. Pelus
From the Department of Microbiology and Immunology and
the Walther Oncology Center, Indiana University School of Medicine, and
the Walther Cancer Institute, Indianapolis, IN.
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.
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