Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease
Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease
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DOI：
10.1182/blood-2009-04-215848
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发表时间：
2010-04-29
期刊：
影响因子：
20.3
通讯作者：
Mohi, M. Golam
中科院分区：
文献类型：
--
作者：
Akada, Hajime;Yan, Dongqing;Mohi, M. Golam
在大多数患有多余性无体病（PV），必需血小板性血小板和原发性骨髓纤维化的患者中发现了JAK2酪氨酸激酶中的体细胞突变（V617F）。然而，这3种临床上不同的脊髓增生性肿瘤（MPN）在这3个临床上不同的JAK2V617F突变的贡献尚不清楚。为了研究JAK2V617F在这些MPN的发病机理中的作用，我们产生了可诱导的JAK2V617F敲入小鼠，其中JAK2V617F的表达受到内源性JAK2启动子的控制。 Expression of heterozygous mouse Jak2V617F evoked all major features of human polycythemia vera (PV), which included marked increase in hemoglobin and hematocrit, increased red blood cells, leukocytosis, thrombocytosis, splenomegaly, reduced serum erythropoietin (Epo) levels and Epo-independent erythroid colonies 。纯合JAK2V617F表达也导致了一种类似PV的疾病，与报性细胞增多症，白细胞增多，中性粒细胞增多症，中性粒细胞增多和血小板性疾病显着，明显的颗粒状祖细胞增长和斑点异常的斑纹型骨膜和高脂肪的骨膜大小相结合。 JAK2V617F表达。生化分析显示JAK2V617F基因剂量依赖性STAT5，AKT和ERK信号通路的激活。我们的条件JAK2V617F敲入小鼠提供了一个出色的模型，可用于进一步了解MPN的分子发病机理，并确定与不同MPN中与JAK2V617F合作的其他遗传事件。 （Blood。2010; 115（17）：3589-3597）
A somatic point mutation (V617F) in the JAK2 tyrosine kinase was found in a majority of patients with polycythemia vera (PV), essential thrombocythemia, and primary myelofibrosis. However, contribution of the JAK2V617F mutation in these 3 clinically distinct myeloproliferative neoplasms (MPNs) remained unclear. To investigate the role of JAK2V617F in the pathogenesis of these MPNs, we generated an inducible Jak2V617F knock-in mouse, in which the expression of Jak2V617F is under control of the endogenous Jak2 promoter. Expression of heterozygous mouse Jak2V617F evoked all major features of human polycythemia vera (PV), which included marked increase in hemoglobin and hematocrit, increased red blood cells, leukocytosis, thrombocytosis, splenomegaly, reduced serum erythropoietin (Epo) levels and Epo-independent erythroid colonies. Homozygous Jak2V617F expression also resulted in a PV-like disease associated with significantly greater reticulocytosis, leukocytosis, neutrophilia and thrombocytosis, marked expansion of erythroid progenitors and Epo-independent erythroid colonies, larger spleen size, and accelerated bone marrow fibrosis compared with heterozygous Jak2V617F expression. Biochemical analyses revealed Jak2V617F gene dosage-dependent activation of Stat5, Akt, and Erk signaling pathways. Our conditional Jak2V617F knock-in mice provide an excellent model that can be used to further understand the molecular pathogenesis of MPNs and to identify additional genetic events that cooperate with Jak2V617F in different MPNs. (Blood. 2010; 115(17): 3589-3597)