Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice
Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice
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DOI：
10.1182/blood-2007-08-107748
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发表时间：
2008-04-15
期刊：
影响因子：
20.3
通讯作者：
Skoda, Radek C.
中科院分区：
文献类型：
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作者：
Tiedt, Ralph;Hao-Shen, Hui;Skoda, Radek C.
JAK 2基因（JAK 2-V617 F）中的获得性体细胞突变存在于大多数骨髓增生性疾病（MPD）患者中。几种表型表现（真性红细胞增多症[PV]、原发性血小板增多症[ET]和原发性骨髓纤维化）可能与相同的突变相关。我们使用人JAK 2基因产生了JAK 2-V617 F转基因小鼠，其中编码激酶结构域的序列以相反的方向放置，并且两侧是反平行的loxP位点。将一个转基因系（FF 1）的小鼠与在造血特异性Vav启动子控制下表达Cre重组酶的转基因小鼠杂交，导致JAK 2-V617 F的表达低于内源性野生型Jak 2。这些小鼠出现了类似于ET的表型，血小板计数显著升高，中度嗜中性粒细胞。用干扰素诱导型MxCre诱导JAK 2-V617 F转基因导致JAK 2-V617 F的表达约等于野生型Jak 2和具有增加的血红蛋白、血小板增多和嗜中性粒细胞增多的PV样表型。通过逆转录病毒转导，小鼠骨髓中较高水平的JAK 2-V617 F导致PV样表型，而无血小板增多。这些数据与突变体与野生型JAK 2的比例对于表型表现至关重要的假设一致。在MPD患者中也发现了类似的相关性。
An acquired somatic mutation in the JAK2 gene (JAK2-V617F) is present in the majority of patients with myeloproliferative disorders (MPDs). Several phenotypic manifestations (polycythemia vera [PV], essential thrombocythemia [ET], and primary myelofibrosis) can be associated with the same mutation. We generated JAK2-V617F transgenic mice using a human JAK2 gene with the sequences encoding the kinase domain placed in the inverse orientation and flanked by antiparallel loxP sites. Crossing mice of one transgenic line (FF1) with transgenic mice expressing Cre-recombinase under the control of the hematopoiesis specific Vav promoter led to expression of JAK2-V617F that was lower than the endogenous wild-type Jak2. These mice developed a phenotype resembling ET with strongly elevated platelet counts and moderate neutrophilia. Induction of the JAK2-V617F transgene with the interferon-inducible MxCre resulted in expression of JAK2-V617F approximately equal to wildtype Jak2 and a PV-Iike phenotype with increased hemoglobin, thrombocytosis, and neutrophilia. Higher levels of JAK2-V617F in mouse bone marrow by retroviral transduction caused a PV-like phenotype without thrombocytosis. These data are consistent with the hypothesis that the ratio of mutant to wild-type JAK2 is critical for the phenotypic manifestation. A similar correlation was also found in patients with MPD.