Constitutive activation of zebrafish Stat5 expands hematopoietic cell populations in vivo.
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AbstractOBJECTIVE: Constitutive activation of Stat5 has been observed in a variety of malignancies, particularly myeloid leukemias. To directly investigate the in vivo consequences of Stat5 perturbation, we expressed constitutively active forms in zebrafish. METHODS: We generated mutants of the zebrafish stat5.1 protein (N646H, H298R/N714F, and N714F) based on previously identified constitutively active mutants of murine Stat5a. The in vitro properties of these mutants were determined using phosphorylation-specific antibodies and luciferase reporter assays, and their in vivo effects were analyzed through microinjection of zebrafish embryos. RESULTS: Two of these stat5.1 mutants (N646H and H298R/N714F) showed increased tyrosine phosphorylation and transactivation activity compared to the wild-type protein. Expression of either mutant led to a range of hematological perturbations, which were more pronounced for the H298R/N714F mutant. Interestingly, expression of wild-type also produced generally similar phenotypes. Further analysis showed that expression of the H298R/N714F mutant led to increased numbers of early and late myeloid cells, erythrocytes, and B cells. Some nonhematopoietic developmental perturbations were also observed, but these were equally prominent with wild-type or mutant forms. CONCLUSION: These data implicate Stat5 activity as a direct critical regulator of hematological cell proliferation, suggesting a causal role for constitutively-active Stat5 in the etiology of hematological malignancies.
CitationExp. Hematol. 2006, 34 (2):179-87
DescriptionKEYWORDS - CLASSIFICATION: analysis;Amino Acid Substitution;Animals;Biology;cytology;Cell Line;Cell Lineage;Cell Proliferation;drug effects;etiology;genetics;Hematologic Diseases;Hematopoietic Stem Cells;Humans;metabolism;mechanisms of carcinogenesis;Molecular Biology;Mutagenesis,Site-Directed;Mutation;pathology;pharmacology;physiology;Phosphorylation;Proteins;Research;STAT5 Transcription Factor;Tyrosine;Zebrafish;Zebrafish Proteins.
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