Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation
Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation
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DOI：
10.1073/pnas.0509714102
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发表时间：
2005-12-27
影响因子：
11.1
通讯作者：
Lodish, H
中科院分区：
文献类型：
--
作者：
Lu, XH;Levine, R;Lodish, H
非受体酪氨酸激酶JAK 2（JAK 2 V617 F）中的复发性体细胞激活突变发生在大多数骨髓增生性疾病患者中，包括真性红细胞增多症、原发性血小板增多症、骨髓纤维化伴髓样化生，以及较不常见的慢性粒单核细胞白血病。我们不理解JAK 2 V617 F突变在髓系而非淋巴系克隆性疾病中特异性的基础，也没有描述JAK 2 V617 F相关骨髓增生性疾病的多效性表型的基础。然而，在相关但临床病理学上不同的骨髓疾病患者中存在相同的突变表明JAK 2 V617 F激酶和其他信号分子之间的相互作用可能影响表达JAK 2 V617 F的造血祖细胞的表型。在这里，我们表明，JAK 2 V617 F突变激酶与同型二聚体I型细胞因子受体，促红细胞生成素受体（EpoR），促血小板生成素受体，或粒细胞集落刺激因子受体的共表达，是必要的造血细胞转化为生长因子的独立性和JAK-STAT信号的非依赖性激活。此外，损害促红细胞生成素介导的JAK 2或STAT 5活化的EpoR突变也损害由JAK 2 V617 F激酶介导的转化，表明JAK 2 V617 F需要细胞因子受体支架用于其转化和信号传导活性。我们的研究结果揭示了JAK 2 V617 F在表达这些I型细胞因子受体的髓系细胞疾病中流行的分子基础，但在不表达这些I型细胞因子受体的淋巴系细胞中不流行。
A recurrent somatic activating mutation in the nonreceptor tyrosine kinase JAK2 (JAK2V617F) occurs in the majority of patients with the myeloproliferative disorders polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, and, less commonly, chronic myelomonocytic leukemia. We do not understand the basis for the specificity of the JAK2V617F mutation in clonal disorders of the myeloid, but not lymphoid, lineage, nor has the basis for the pleiotropic phenotype of JAK2V617F-associated myeloproliferative disorders been delineated. However, the presence of the identical mutation in patients with related, but clinicopathologically distinct, myeloid disorders suggests that interactions between the JAK2V617F kinase and other signaling molecules may influence the phenotype of hematopoietic progenitors expressing JAK2V617F. Here, we show that coexpression of the JAK2V617F mutant kinase with a homodimeric Type I cytokine receptor, the erythropoietin receptor (EpoR), the thrombopoietin receptor, or the granulocyte colony-stimulating-factor receptor, is necessary for transformation of hematopoietic cells to growth-factor independence and for hormone-independent activation of JAK-STAT signaling. Furthermore, EpoR mutations that impair erythropoietin-mediated JAK2 or STAT5 activation also impair transformation mediated by the JAK2V617F kinase, indicating that JAK2V617F requires a cytokine receptor scaffold for its transforming and signaling activities. Our results reveal the molecular basis for the prevalence of JAK2V617F in diseases of myeloid lineage cells that express these Type I cytokine receptors but not in lymphoid lineage cells that do not.