Gain-of-Function of Stat5 Leads to Excessive Granulopoiesis and Lethal Extravasation of Granulocytes to the Lung

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.

信号转导与转录激活因子5（Signal Transducer and Activator of Transcription 5，Stat5）在正常造血过程以及多种造血系统恶性肿瘤中发挥关键作用。Stat5的缺失会导致细胞因子介导的祖细胞及其沿红系、淋巴系与髓系等主要造血谱系分化的子代细胞的增殖与存活能力受损。Stat5的过表达与持续激活足以在移植模型中诱发肿瘤转化并形成多系白血病。然而目前尚不清楚该信号转导分子的持续激活对于造血系统恶性肿瘤的维持是否必需。
为解决这一科学问题，我们构建了可在配体调控下于造血祖细胞及其分化谱系中表达Stat5超激活突变体的转基因小鼠。与移植模型不同，在内源野生型Stat5等位基因存在的情况下，突变型Stat5的表达并未对正常造血功能产生负面影响。但在携带Stat5a/b低功能等位基因的小鼠中，该信号转导分子的功能获得性表型会导致循环粒细胞数量异常升高，进而引发严重的气道阻塞。在患病动物体内下调超激活型Stat5的表达可恢复正常的粒细胞生成，同时能够快速清除肺部浸润的粒细胞。此外，我们证实Stat5可通过细胞自主方式促进重度粒细胞增多症的发生与维持。
本研究结果表明，Stat5的功能获得性会引发过度的粒细胞生成，并延长循环粒细胞的存活时间。综上，我们的研究结果强调了Stat5在造血过程中维持髓系与淋巴系细胞平衡的核心作用，并为Stat5在粒细胞增多症相关肺功能异常中的功能提供了直接实验证据。