Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders
Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders
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DOI：
10.1016/s0140-6736(05)71142-9
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发表时间：
2005-03-19
期刊：
影响因子：
168.9
通讯作者：
Green, AR
中科院分区：
文献类型：
--
作者：
Baxter, EJ;Scott, LM;Green, AR
背景人类骨髓增生性疾病是一系列克隆性恶性血液病，主要包括真性红细胞增多症、原发性血小板增多症和特发性骨髓纤维化。这些疾病的分子发病机制尚不清楚，但酪氨酸激酶与几种相关疾病有关。我们研究了细胞质酪氨酸激酶JAK2在骨髓增生性疾病患者中的作用。方法我们从真性红细胞增多症、原发性血小板增多症或特发性骨髓纤维化患者中获得DNA样本。JAK2的编码外显子从外周血粒细胞、T细胞或两者中双向测序。等位基因特异性PCR、分子细胞遗传学研究、微卫星PCR、Affyestine单核苷酸多态性阵列分析和菌落测定对患者亚组进行。在73例真性红细胞增多症患者中的71例（97%）、51例原发性血小板增多症患者中的29例（57%）、16例特发性骨髓纤维化患者中有8例（50%）。该突变是获得性的，存在于不同比例的粒细胞中，改变了存在于负调控JH2结构域中的高度保守的缬氨酸，并预测会失调激酶活性。它在大多数患者中是杂合的，在一个子集中是纯合的，这是有丝分裂重组的结果，并出现在能够产生红系和髓系细胞的多能祖细胞中。突变是存在于所有的红细胞生成素独立的红细胞colones.Interpretation一个单一的获得性突变JAK2指出，在超过一半的骨髓增生性疾病的患者。它的存在于所有的红细胞生成素独立的红细胞集落证明了与生长因子超敏反应，这些disorders.Relevance的关键生物学特征的联系实践的Val617Phe JAK2突变的鉴定奠定了基础，新的方法来诊断，分类和治疗骨髓增生性疾病。
Background Human myeloproliferative disorders form a range of clonal haematological malignant diseases, the main members of which are polycythaemia vera, essential thrombocythaemia, and idiopathic myelofibrosis. The molecular pathogenesis of these disorders is unknown, but tyrosine kinases have been implicated in several related disorders. We investigated the role of the cytoplasmic tyrosine kinase JAK2 in patients with a myeloproliferative disorder.Methods We obtained DNA samples from patients with polycythaemia vera, essential thrombocythaemia, or idiopathic myelofibrosis. The coding exons of JAK2 were bidirectionally sequenced from peripheral-blood granulocytes, T cells, or both. Allele-specific PCR, molecular cytogenetic studies, microsatellite PCR, Affymetrix single nucleotide polymorphism array analyses, and colony assays were undertaken on subgroups of patients.Findings A single point mutation (Val617Phe) was identified in JAK2 in 71 (97%) of 73 patients with polycythaemia vera, 29 (57%) of 51 with essential thrombocythaemia, and eight (50%) of 16 with idiopathic myelofibrosis. The mutation is acquired, is present in a variable proportion of granulocytes, alters a highly conserved valine present in the negative regulatory JH2 domain, and is predicted to dysregulate kinase activity. It was heterozygous in most patients, homozygous in a subset as a result of mitotic recombination, and arose in a multipotent progenitor capable of giving rise to erythroid and myeloid cells. The mutation was present in all erythropoietin-independent erythroid colonies.Interpretation A single acquired mutation of JAK2 was noted in more than half of patients with a myeloproliferative disorder. Its presence in all erythropoietin-independent erythroid colonies demonstrates a link with growth factor hypersensitivity, a key biological feature of these disorders.Relevance to practice Identification of the Val617Phe JAK2 mutation lays the foundation for new approaches to the diagnosis, classification, and treatment of myeloproliferative disorders.