STAT5 activation contributes to growth and viability in Bcr/Abl-transformed cells

The transcription factor STAT5 is constitutively tyrosine phosphorylated and activated after transformation of hematopoietic cells by p210Bcr/Abl, A truncated form of STAT5B (Delta STAT5; as, 1-683) that lacks tyrosine 699 and the transcriptional activation domain was introduced into Ba/F3p210 cells under the control of a tetracycline-inducible promoter. Treatment of these cells with doxycycline, a tetracycline analogue, induced expression of Delta STAT5 and inhibited STAT5-dependent transcription. Delta STAT5 coprecipitated with STAT5 and decreased Bcr/Abl-dependent tyrosine phosphorylation of endogenous STAT5. Induction of Delta STAT5 inhibited growth of Ba/F3p210 cells (26%-52% of control levels at 4 days) but did not cause cell-cycle arrest. Delta STAT5 reduced viability of Ba/F3p210 cells and increased sensitivity of the cells to the cytotoxic drugs hydroxyurea and cytarabine, These results indicate that high-level expression of Delta STAT5, as achieved here by using a tetracycline-inducible promoter, inhibits STAT5 activity, reduces the growth rate of Ba/F3p210 cells by inhibiting viability, and results in increased sensitivity to chemotherapeutic drugs, It Is therefore likely that STAT5 activation plays a role in the transformation of hematopoietic cell lines by p210Bcr/Abl. (C) 2000 by The American Society of Hematology.