JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis.
JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis.
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DOI：
10.1056/nejmoa065202
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发表时间：
2007-02-01
期刊：
影响因子：
--
通讯作者：
Green AR
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文献类型：
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作者：
Scott LM;Tong W;Levine RL;Scott MA;Beer PA;Stratton MR;Futreal PA;Erber WN;McMullin MF;Harrison CN;Warren AJ;Gilliland DG;Lodish HF;Green AR
在真性红细胞增多症、原发性血小板增多症和特发性骨髓纤维化患者中，V617F突变导致Janus激酶(JAK)2基因(JAK2)617位的苯丙氨酸取代Valine。然而，在没有V617F突变的患者中，这些骨髓增生性疾病的分子基础尚不清楚。我们在V617F阴性真性红细胞增多症或特发性红细胞增多症患者中寻找JAK和信号转导和转录激活因子(STAT)基因家族成员的新突变。在骨髓移植的小鼠模型中，对这些突变进行了生化表征。我们在10名V617F阴性患者中发现了四个影响JAK2外显子12的体细胞功能获得突变。那些JAK2外显子12突变的患者表现为孤立的红细胞增多症和独特的骨髓形态，其中一些患者的血清促红细胞生成素水平也降低。在没有外源促红细胞生成素的情况下，可以从他们的血液样本中培养出红系集落。所有这些红系集落都是突变的杂合子，而突变纯合子的集落出现在大多数V617F阳性真性红细胞增多症患者中。表达小鼠促红细胞生成素受体并携带外显子12突变的BaF3细胞可以在没有添加白细胞介素3的情况下增殖。与野生型JAK2或V617F JAK2转导的细胞相比，它们还显示出JAK2和细胞外调节激酶1和2的磷酸化增强。在12号外显子突变中，有3个突变包括JAK2基因第539位亮氨酸取代赖氨酸。在逆转录病毒骨髓移植的小鼠模型中，这种突变导致了骨髓增殖性表型，包括红细胞增多。JAK2外显子12突变定义了一种独特的骨髓增殖性综合征，影响目前接受真性红细胞增多症或特发性红细胞增多症诊断的患者。
The V617F mutation, which causes the substitution of phenylalanine for valine at position 617 of the Janus kinase (JAK) 2 gene (JAK2), is often present in patients with polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. However, the molecular basis of these myeloproliferative disorders in patients without the V617F mutation is unclear. We searched for new mutations in members of the JAK and signal transducer and activator of transcription (STAT) gene families in patients with V617F-negative polycythemia vera or idiopathic erythrocytosis. The mutations were characterized biochemically and in a murine model of bone marrow transplantation. We identified four somatic gain-of-function mutations affecting JAK2 exon 12 in 10 V617F-negative patients. Those with a JAK2 exon 12 mutation presented with an isolated erythrocytosis and distinctive bone marrow morphology, and several also had reduced serum erythropoietin levels. Erythroid colonies could be grown from their blood samples in the absence of exogenous erythropoietin. All such erythroid colonies were heterozygous for the mutation, whereas colonies homozygous for the mutation occur in most patients with V617F-positive polycythemia vera. BaF3 cells expressing the murine erythropoietin receptor and also carrying exon 12 mutations could proliferate without added interleukin-3. They also exhibited increased phosphorylation of JAK2 and extracellular regulated kinase 1 and 2, as compared with cells transduced by wild-type JAK2 or V617F JAK2. Three of the exon 12 mutations included a substitution of leucine for lysine at position 539 of JAK2. This mutation resulted in a myeloproliferative phenotype, including erythrocytosis, in a murine model of retroviral bone marrow transplantation. JAK2 exon 12 mutations define a distinctive myeloproliferative syndrome that affects patients who currently receive a diagnosis of polycythemia vera or idiopathic erythrocytosis.