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Abstract：
Emergency granulopoiesis occurs in response to infectious or inflammatory challenge and is a component of the innate immune response. Some molecular events involved in initiating emergency granulopoiesis are known, but termination of this process is less well defined. In this study, we found that the interferon consensus sequence binding protein (Icsbp/Irf8) was required to terminate emergency granulopoiesis. Icsbp is an interferon regulatory transcription factor with leukemia suppressor activity. Expression of Icsbp is decreased in chronic myeloid leukemia, and Icsbp(-/-) mice exhibit progressive granulocytosis with evolution to blast crisis, similar to the course of human chronic myeloid leukemia. In this study, we found aberrantly sustained granulocyte production in Icsbp(-/-) mice after stimulation of an emergency granulopoiesis response. Icsbp represses transcription of the genes encoding Fas-associated phosphatase 1 (Fap1) and growth arrest-specific 2 (Gas2) and activates genes encoding Fanconi C and F. After stimulation of emergency granulopoiesis, we found increased and sustained expression of Fap1 and Gas2 in bone marrow myeloid progenitor cells from Icsbp(-/-) mice in comparison with the wild type. This was associated with resistance to Fas-induced apoptosis and increased β-catenin activity in these cells. We also found that repeated episodes of emergency granulopoiesis accelerated progression to acute myeloid leukemia in Icsbp(-/-) mice. This was associated with impaired Fanconi C and F expression and increased sensitivity to DNA damage in bone marrow myeloid progenitors. Our results suggest that impaired Icsbp expression enhances leukemogenesis by deregulating processes that normally limit granulocyte expansion during the innate immune response.
摘要：
紧急粒细胞生成发生在对感染性或炎性攻击的响应中,并且是先天免疫应答的组成部分。一些涉及启动紧急粒细胞生成的分子事件是已知的，但是这个过程的终止不太明确。在这项研究中,我们发现,终止急诊粒细胞生成需要干扰素共有序列结合蛋白(Icsbp/Irf8).Icsbp是一种具有白血病抑制活性的干扰素调节转录因子。Icsbp在慢性粒细胞白血病中的表达降低，Icsbp（-/-）小鼠表现出进行性粒细胞缺乏症，并进化为爆炸危机，与人类慢性粒细胞白血病的病程相似。在这项研究中,我们发现Icsbp(-/-)小鼠在刺激紧急粒细胞生成反应后产生异常持续的粒细胞.Icsbp抑制编码Fas相关磷酸酶1（Fap1）和生长停滞特异性2（Gas2）的基因的转录，并激活编码FanconiC和F的基因。我们发现与野生型相比,Fap1和Gas2在Icsbp(-/-)小鼠骨髓骨髓祖细胞中的表达增加和持续增加.这与这些细胞对Fas诱导的细胞凋亡的抗性和β-catenin活性的增加有关。我们还发现，反复发作的紧急粒细胞生成加速了Icsbp（-/-）小鼠急性髓细胞性白血病的进展。这与FanconiC和F表达受损以及对骨髓骨髓祖细胞DNA损伤的敏感性增加有关。我们的结果表明，受损的Icsbp表达通过失调过程来增强白血病的发生，这些过程通常会限制先天免疫反应期间的粒细胞扩增。
