Scott Linda M, Tong Wei, Levine Ross L, Scott Mike A, Beer Philip A, Stratton Michael R, Futreal P Andrew, Erber Wendy N, McMullin Mary Frances, Harrison Claire N, Warren Alan J, Gilliland D Gary, Lodish Harvey F, Green Anthony R
University of Cambridge, Cambridge, United Kingdom.
N Engl J Med. 2007 Feb 1;356(5):459-68. doi: 10.1056/NEJMoa065202.
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.
V617F突变导致Janus激酶（JAK）2基因（JAK2）第617位的缬氨酸被苯丙氨酸取代，该突变常见于真性红细胞增多症、原发性血小板增多症和原发性骨髓纤维化患者中。然而，V617F突变阴性的骨髓增殖性疾病患者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和信号转导及转录激活因子（STAT）基因家族成员中的新突变。对这些突变进行生化特征分析，并在骨髓移植小鼠模型中进行研究。
我们在10例V617F阴性患者中鉴定出4个影响JAK2外显子12的体细胞功能获得性突变。携带JAK2外显子12突变的患者表现为单纯红细胞增多症和独特的骨髓形态，部分患者血清促红细胞生成素水平也降低。在无外源性促红细胞生成素的情况下，可从他们的血样中培养出红系集落。所有这些红系集落对该突变均为杂合子，而大多数V617F阳性真性红细胞增多症患者的集落对该突变是纯合子。表达小鼠促红细胞生成素受体且携带外显子12突变的BaF3细胞在无白细胞介素-3添加的情况下能够增殖。与野生型JAK2或V617F JAK2转导的细胞相比，它们还表现出JAK2以及细胞外调节激酶1和2的磷酸化增加。其中3个外显子12突变包括JAK2第539位的赖氨酸被亮氨酸取代。在逆转录病毒骨髓移植小鼠模型中，该突变导致骨髓增殖表型，包括红细胞增多症。
JAK2外显子12突变定义了一种独特的骨髓增殖综合征，影响目前被诊断为真性红细胞增多症或特发性红细胞增多症的患者。
