Critical role of Jak2 in the maintenance and function of adult hematopoietic stem cells.
Critical role of Jak2 in the maintenance and function of adult hematopoietic stem cells.
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DOI：
10.1002/stem.1711
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发表时间：
2014-07
期刊：
影响因子：
5.2
通讯作者：
Mohi, Golam
中科院分区：
文献类型：
--
作者：
Akada, Hajime;Akada, Saeko;Hutchison, Robert E.;Sakamoto, Kazuhito;Wagner, Kay-Uwe;Mohi, Golam
关键词：
Jak 2是非受体蛋白酪氨酸激酶的Janus激酶家族的成员，响应于多种细胞因子而被激活，并且在细胞的存活和增殖中起作用。在大多数骨髓增生性肿瘤患者中发现了激活JAK 2 V617 F突变，并且用Jak 2抑制剂治疗的患者显示出显著的造血毒性。然而，Jak 2在成体造血干细胞（HSC）中的作用尚未明确阐明。使用条件性Jak 2敲除等位基因，我们发现Jak 2缺失导致HSC/祖细胞的快速丧失，导致成年小鼠的骨髓衰竭和早期致死。Jak 2缺陷导致HSC功能显著受损，并且突变的HSC在受体动物中重建造血方面严重缺陷。Jak 2缺陷还导致HSC富集的LSK（Lin−Sca-1+c-kit+）细胞中显著的凋亡和静止丧失。缺乏Jak 2的LSK细胞表现出升高的活性氧水平和增强的p38 MAPK活化。突变型LSK细胞也表现出缺陷的Stat 5，Erk和Akt激活血小板生成素和干细胞因子的反应。基因表达分析显示，在Jak 2缺陷的LSK细胞中，与HSC静止和自我更新相关的基因显著下调。这些数据表明，Jak 2在成体HSC的维持和功能中起着关键作用。
Jak2, a member of the Janus kinase family of non-receptor protein tyrosine kinases, is activated in response to a variety of cytokines, and functions in survival and proliferation of cells. An activating JAK2V617F mutation has been found in most patients with myeloproliferative neoplasms, and patients treated with Jak2 inhibitors show significant hematopoietic toxicities. However, the role of Jak2 in adult hematopoietic stem cells (HSCs) has not been clearly elucidated. Using a conditional Jak2 knockout allele, we have found that Jak2 deletion results in rapid loss of HSCs/progenitors leading to bone marrow failure and early lethality in adult mice. Jak2 deficiency causes marked impairment in HSC function, and the mutant HSCs are severely defective in reconstituting hematopoiesis in recipient animals. Jak2 deficiency also causes significant apoptosis and loss of quiescence in HSC-enriched LSK (Lin−Sca-1+c-kit+) cells. Jak2-deficient LSK cells exhibit elevated reactive oxygen species levels and enhanced p38 MAPK activation. Mutant LSK cells also show defective Stat5, Erk and Akt activation in response to thrombopoietin and stem cell factor. Gene expression analysis reveals significant downregulation of genes related to HSC quiescence and self-renewal in Jak2-deficient LSK cells. These data suggest that Jak2 plays a critical role in the maintenance and function of adult HSCs.
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影响因子：
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