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

• Published in: Blood 2000-03, Vol.95 (6), p.2118-2125
• Main Authors: Sillaber, Christian, Gesbert, Franck, Frank, David A., Sattler, Martin, Griffin, James D.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Antimetabolites, Antineoplastic - pharmacology; Biological and medical sciences; Cell Cycle; Cell Division; Cell Line; Cell Line, Transformed; Cell Survival; Cytarabine - pharmacology; DNA, Complementary - metabolism; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Dose-Response Relationship, Drug; Doxycycline - pharmacology; Enzyme Inhibitors - pharmacology; Fusion Proteins, bcr-abl - metabolism; Genes, Reporter; Hematologic and hematopoietic diseases; Hydroxyurea - pharmacology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Milk Proteins; Mutation; Phosphorylation; Promoter Regions, Genetic; STAT5 Transcription Factor; Time Factors; Trans-Activators - metabolism; Trans-Activators - physiology; Tyrosine - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V95.6.2118

The transcription factor STAT5 is constitutively tyrosine phosphorylated and activated after transformation of hematopoietic cells by p210Bcr/Abl. A truncated form of STAT5B (▵STAT5; aa, 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 ▵STAT5 and inhibited STAT5-dependent transcription. ▵STAT5 coprecipitated with STAT5 and decreased Bcr/Abl-dependent tyrosine phosphorylation of endogenous STAT5. Induction of ▵STAT5 inhibited growth of Ba/F3p210 cells (26%-52% of control levels at 4 days) but did not cause cell-cycle arrest. ▵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 ▵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.