Abstract
The Signal Transducer and Activator of Transcription 5 (Stat5) plays a significant role in normal hematopoiesis and a variety of hematopoietic malignancies. Deficiency in Stat5 causes impaired cytokine-mediated proliferation and survival of progenitors and their differentiated descendants along major hematopoietic lineages such as erythroid, lymphoid, and myeloid cells. Overexpression and persistent activation of Stat5 are sufficient for neoplastic transformation and development of multi-lineage leukemia in a transplant model. Little is known, however, whether a continuous activation of this signal transducer is essential for the maintenance of hematopoietic malignancies. To address this issue, we developed transgenic mice that express a hyperactive mutant of Stat5 in hematopoietic progenitors and derived lineages in a ligand-controlled manner. In contrast to the transplant model, expression of mutant Stat5 did not adversely affect normal hematopoiesis in the presence of endogenous wildtype Stat5 alleles. However, the gain-of-function of this signal transducer in mice that carry Stat5a/b hypomorphic alleles resulted in abnormally high numbers of circulating granulocytes that caused severe airway obstruction. Downregulation of hyperactive Stat5 in diseased animals restored normal granulopoiesis, which also resulted in a swift clearance of granulocytes from the lung. Moreover, we demonstrate that Stat5 promotes the initiation and maintenance of severe granulophilia in a cell autonomous manner. The results of this study show that the gain-of-function of Stat5 causes excessive granulopoiesis and prolonged survival of granulocytes in circulation. Collectively, our findings underline the critical importance of Stat5 in maintaining a normal balance between myeloid and lymphoid cells during hematopoiesis, and we provide direct evidence for a function of Stat5 in granulophilia–associated pulmonary dysfunction.
Highlights
Signal Transducers and Activators of Transcription 5 (Stat5a and Stat5b) mediate extracellular signals from a variety of cytokine receptors and are essential for the growth and differentiation of many cell types including those of hematopoietic lineages
We developed transgenic mice in which the expression of exogenous Signal Transducer and Activator of Transcription 5 (Stat5) can be targeted to hematopoietic stem cells and derived lineages in a ligand regulatable manner
The immunoblot analysis revealed that the MMTV-tTA-mediated transactivation of the TetO-Stat5 transgene occurred in multiple secretory organs, and overexpression of exogenous Stat5 was readily detectable in the salivary gland and in the prostate (Fig. 1E)
Summary
Signal Transducers and Activators of Transcription 5 (Stat5a and Stat5b) mediate extracellular signals from a variety of cytokine receptors and are essential for the growth and differentiation of many cell types including those of hematopoietic lineages. Mice deficient in either Stat5a or Stat5b show defects in the prolactin-induced functional differentiation of the mammary gland [1] or in sexual dimorphism in the control of body size mediated by growth hormone [2]. Subsequent studies using Stat5a/Stat5b conditional knockout mice showed that the combined functions of these evolutionarily conserved transcription factors are critical for the homeostasis and differentiation of hematopoietic stem cells and derived descendants along the lymphoid lineage [7,8,9,10,11]. Stat is required for granulocyte macrophage colonystimulating factor receptor (GM-CSF) signaling and controls granulopoiesis by promoting the generation of granulocytes from granulocyte-macrophage progenitors (GMPs) as well as the survival of mature neutrophils [12,13]
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