Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3
Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3
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DOI：
10.1073/pnas.0603507103
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发表时间：
2006-06-27
影响因子：
11.1
通讯作者：
Wasik, Mariusz A.
中科院分区：
文献类型：
--
作者：
Kasprzycka, Monika;Marzec, Michal;Wasik, Mariusz A.
由致癌嵌合核磷蛋白/间变性淋巴瘤激酶（NPM/ALK）酪氨酸激酶介导的恶性细胞转化的机制仍然只有部分了解。在这里，我们报告了NPM/ALK携带T细胞淋巴瘤（ALK+TCL）细胞分泌IL-10和TGF-β并表达FoxP 3，表明其T调节（Treg）细胞表型。分泌的IL-10抑制正常免疫、CD 3/CD 28刺激的外周血单核细胞的增殖，并增强ALK+TCL细胞的活力。受影响细胞的Treg表型严格依赖于NPM/ALK表达和功能，如通过将激酶转染到BaF 3细胞中并抑制其在ALK+TCL细胞中的酶活性和表达所证明的。NPM/ALK反过来通过激活其关键信号传导因子、信号转导子和转录激活因子3（STAT 3）诱导表型。这些发现确定了NPM/ALK介导的肿瘤发生机制，其基于转化的CD 4（+）T细胞的Treg表型的诱导。这些结果还为治疗性靶向ALK+TCL中的嵌合激酶和/或STAT 3提供了额外的基本原理。
The mechanisms of malignant cell transformation mediated by the oncogenic, chimeric nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) tyrosine kinase remain only partially understood. Here we report that the NPM/ALK-carrying T cell lymphoma (ALK+TCL) cells secrete IL-10 and TGF-beta and express FoxP3, indicating their T regulatory (Treg) cell phenotype. The secreted IL-10 suppresses proliferation of normal immune, CD3/CD28-stimulated peripheral blood mononuclear cells and enhances viability of the ALK+TCL cells. The Treg phenotype of the affected cells is strictly dependent on NPM/ALK expression and function as demonstrated by transfection of the kinase into BaF3 cells and inhibition of its enzymatic activity and expression in ALK+TCL cells. NPM/ALK, in turn, induces the phenotype through activation of its key signal transmitter, signal transducer and activator of transcription 3 (STAT3). These findings identify a mechanism of NPM/ALK-mediated oncogenesis based on induction of the Treg phenotype of the transformed CD4(+) T cells. These results also provide an additional rationale to therapeutically target the chimeric kinase and/or STAT3 in ALK+TCL.