The Interferon Consensus Sequence Binding Protein (Icsbp/Irf8) Is Required for Termination of Emergency Granulopoiesis
The Interferon Consensus Sequence Binding Protein (Icsbp/Irf8) Is Required for Termination of Emergency Granulopoiesis
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DOI：
10.1074/jbc.m115.681361
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发表时间：
2016-02-19
影响因子：
4.8
通讯作者：
Eklund, Elizabeth A.
中科院分区：
文献类型：
--
作者：
Hu, Liping;Huang, Weiqi;Eklund, Elizabeth A.
紧急粒细胞生成是对感染或炎症攻击的反应，是先天免疫反应的一个组成部分。一些参与启动紧急粒细胞生成的分子事件是已知的，但该过程的终止不太明确。在这项研究中，我们发现干扰素共有序列结合蛋白（Icsbp/Irf 8）是终止紧急粒细胞生成所必需的。Icsbp是一种具有白血病抑制活性的干扰素调节转录因子。在慢性粒细胞白血病中，ICSbp的表达降低，并且ICSbp（-/-）小鼠表现出进行性粒细胞增多症，并演变为急变，类似于人类慢性粒细胞白血病的过程。在这项研究中，我们发现异常持续的粒细胞产生ICSBP（-/-）小鼠刺激后，紧急粒细胞生成反应。Icsbp抑制编码Fas相关磷酸酶1（Fap 1）和生长停滞特异性2（Gas 2）的基因的转录，并激活编码Fanconi C和F的基因。在刺激紧急粒细胞生成后，我们发现与野生型相比，来自Icsbp（-/-）小鼠的骨髓髓系祖细胞中Fap 1和Gas 2的表达增加并持续。这与抵抗Fas诱导的细胞凋亡和这些细胞中β-连环蛋白活性增加有关。我们还发现，反复发作的紧急粒细胞生成加速进展为急性髓性白血病在ICSBP（-/-）小鼠。这与Fanconi C和F表达受损以及骨髓髓系祖细胞对DNA损伤的敏感性增加有关。我们的研究结果表明，受损的ICSBP表达增强白血病的解除管制过程中，通常限制粒细胞扩增的先天免疫反应。
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 -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.