Antiapoptotic activity of Stat5 required during terminal stages of myeloiddifferentiation

Stat5 is activated by multiple receptors of hematopoietic cytokines. To stu dy its role during hematopoiesis, we have generated primary chicken myelobl asts expressing different dominant-negative (dn) alleles of Stat5. This cau sed a striking inability to generate mature cells, due to massive apoptosis during differentiation. Bcl-2 was able to rescue differentiating cells exp ressing dnStat5 from apoptosis, suggesting that during cytokine-dependent d ifferentiation the main function of the protein is to ensure cell survival. Our findings with dnStat5-expressing chicken myeloblasts were confirmed wi th primary hematopoietic cells from Stat5a/Stat5b-deficient mice. Bone marr ow cells from these animals displayed a strong increase in apoptotic cell d eath during GM-CSF-dependent functional maturation in vitro. The antiapopto tic protein Bcl-x was induced by GM-CSF and IL-3 in a Stat5-dependent fashi on. Ectopic expression of Bcl-x rescued Stat5-deficient bone marrow cells f rom apoptosis, indicating that Stat5 promotes the survival of myeloid proge nitor cells through its ability to induce transcription of the bcl-x gene. Finally, the recruitment of myeloid cells to inflammatory sites was found s trongly impeded in Stat5-deficient mice. Taken together, our findings sugge st that Stat5 may promote cytokine-dependent survival and proliferation of differentiating myeloid progenitor cells in stress or pathological situatio ns, such as inflammation.