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Vol. 14, No. 2, pp. 232-244, January 15, 2000
1 Institute of Molecular Pathology, Vienna Biocenter,
A-1030 Vienna, Austria; 2 Institute of Microbiology and
Genetics, Vienna Biocenter, A-1030 Vienna, Austria; 3 Howard
Hughes Medical Institute and 4 Department of Biochemistry, St.
Jude Children's Research Hospital, Memphis, Tennessee 38105 USA
Stat5 is activated by multiple receptors of hematopoietic cytokines.
To study its role during hematopoiesis, we have generated primary
chicken myeloblasts expressing different dominant-negative (dn) alleles
of Stat5. This caused a striking inability to generate mature cells,
due to massive apoptosis during differentiation. Bcl-2 was able to
rescue differentiating cells expressing dnStat5 from apoptosis,
suggesting that during cytokine-dependent differentiation the main
function of the protein is to ensure cell survival. Our findings with
dnStat5-expressing chicken myeloblasts were confirmed with primary
hematopoietic cells from Stat5a/Stat5b-deficient mice.
Bone marrow cells from these animals displayed a strong increase in
apoptotic cell death during GM-CSF-dependent functional maturation in
vitro. The antiapoptotic protein Bcl-x was induced by GM-CSF and IL-3
in a Stat5-dependent fashion. Ectopic expression of Bcl-x rescued
Stat5-deficient bone marrow cells from apoptosis, indicating that Stat5
promotes the survival of myeloid progenitor cells through its ability
to induce transcription of the bcl-x gene. Finally, the
recruitment of myeloid cells to inflammatory sites was found strongly
impeded in Stat5-deficient mice. Taken together, our findings suggest
that Stat5 may promote cytokine-dependent survival and proliferation of
differentiating myeloid progenitor cells in stress or pathological
situations, such as inflammation.
[Key Words: Stat5; hematopoiesis; apoptosis; myeloid differentiation]
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