Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
PLoS One. 2013;8(4):e60902. doi: 10.1371/journal.pone.0060902. Epub 2013 Apr 2.
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.
信号转导子和转录激活子 5（Stat5）在正常造血和多种造血恶性肿瘤中发挥重要作用。Stat5 的缺失会导致祖细胞及其分化后代对细胞因子介导的增殖和存活受损，这些祖细胞和分化后代沿着主要造血谱系，如红系、淋巴系和髓系细胞分化。Stat5 的过度表达和持续激活足以在移植模型中导致多谱系白血病的肿瘤转化和发展。然而，人们对这种信号转导物的持续激活是否对维持造血恶性肿瘤至关重要知之甚少。为了解决这个问题，我们开发了一种转基因小鼠，该小鼠以配体控制的方式在造血祖细胞及其衍生谱系中表达 Stat5 的一种高活性突变体。与移植模型不同的是，在存在内源性野生型 Stat5 等位基因的情况下，突变 Stat5 的表达不会对正常造血产生不利影响。然而，在携带 Stat5a/b 功能不全等位基因的小鼠中，这种信号转导物的功能获得导致循环粒细胞数量异常增加，导致严重的气道阻塞。在患病动物中下调高活性 Stat5 可恢复正常粒细胞生成，也可迅速清除肺部的粒细胞。此外，我们证明 Stat5 以细胞自主的方式促进严重嗜中性粒细胞增多症的起始和维持。本研究结果表明，Stat5 的功能获得导致过度的粒细胞生成和循环中粒细胞的存活时间延长。总之，我们的研究结果强调了 Stat5 在造血过程中维持骨髓细胞和淋巴样细胞之间正常平衡的重要性，并为 Stat5 在与嗜中性粒细胞增多相关的肺功能障碍中的作用提供了直接证据。
