文章：

JAK2在骨髓增生性疾病的发病机制和治疗中的作用

Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders

原文发布日期：2007-09-01

DOI: 10.1038/nrc2210

类型: Review Article

开放获取: 否

要点：

1. Acquisition of the constitutively active Janus kinase 2 (JAK2)V617F mutation occurs in almost all patients with polycythaemia vera (PV) and in a significant number of patients with essential thombocythaemia (ET) and primary myelofibrosis (PMF).
2. JAK2V617F is a constitutively active tyrosine kinase that activates signal transducer and activator of transcription (Stat), mitogen activated protein kinase (MAPK) and phosphotidylinositol 3-kinase (PI3K) signalling pathways, and transforms haematopoietic progenitors.
3. The identification of JAK2V617F has had a significant impact on the classification, diagnosis and prognosis of PV, ET and PMF.
4. Gain-of-function mutations in JAK2 exon 12 and in the thrombopoietin receptor are observed in some patients with JAK2V617F-negative myeloproliferative disorders (MPD), suggesting constitutive activation of JAK2 signalling is central to the pathogenesis of PV, ET and PMF.
5. The presence of a single disease allele in related, but clinically distinct MPD indicates that additional genetic events contribute to the pathogenesis of these disorders.
6. The discovery of JAK2V617F has led to the development of selective JAK2 inhibitors for the treatment of PV, ET and PMF.

要点翻译：

1. 几乎所有真性红细胞增多症（PV）患者以及相当数量的原发性血小板增多症（ET）和原发性骨髓纤维化（PMF）患者中，均会出现持续活性的Janus激酶2（JAK2）V617F突变的获得。
2. JAK2V617F是一种持续活性的酪氨酸激酶，能够激活信号转导与转录激活因子（Stat）、丝裂原活化蛋白激酶（MAPK）以及磷脂酰肌醇3-激酶（PI3K）信号通路，并转化造血祖细胞。
3. JAK2V617F的发现对PV、ET和PMF的分类、诊断和预后产生了重大影响。
4. 在一些JAK2V617F阴性的骨髓增殖性疾病（MPD）患者中，观察到JAK2外显子12和血小板生成素受体中的功能获得性突变，这表明JAK2信号的持续激活是PV、ET和PMF发病机制的核心。
5. 在相关但临床不同的MPD中存在单一疾病等位基因，表明其他遗传事件也参与了这些疾病的发病机制。
6. JAK2V617F的发现推动了选择性JAK2抑制剂的开发，用于治疗PV、ET和PMF。

英文摘要：

The myeloproliferative disorders polycythaemia vera (PV), essential thombocythaemia (ET), and primary myelofibrosis (PMF) are clonal disorders of multipotent haematopoietic progenitors. The genetic cause of these diseases was not known until 2005, when several independent groups demonstrated that most patients with PV, ET and PMF acquire a single point mutation in the cytoplasmic tyrosine kinase JAK2 (JAK2V617F). These discoveries have changed the landscape for diagnosis and classification of PV, ET and PMF, and show the ability of genomic technologies to identify new molecular targets in human malignancies with pathogenetic, diagnostic and therapeutic significance.

摘要翻译： 

骨髓增殖性疾病中的真性红细胞增多症（PV）、原发性血小板增多症（ET）和原发性骨髓纤维化（PMF）是多能造血祖细胞的克隆性疾病。直到2005年，这些疾病的遗传病因才被揭示：多个独立研究小组发现，大多数PV、ET和PMF患者在细胞质酪氨酸激酶JAK2中获得一个点突变（JAK2V617F）。这些发现改变了PV、ET和PMF的诊断与分类格局，也展示了基因组技术在人类恶性肿瘤中发现具有发病机制、诊断和治疗意义的新分子靶点的能力。

原文链接：

Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders