Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway
Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway
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DOI：
10.1182/blood.v96.13.4319
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发表时间：
2000-12-15
期刊：
影响因子：
20.3
通讯作者：
Duyster, J
中科院分区：
文献类型：
--
作者：
Bai, RY;Tao, OY;Duyster, J
超过一半的间变性大细胞淋巴瘤（ALCL）具有染色体易位t（2;5），导致由核仁磷蛋白核磷蛋白（NPM）和间变性淋巴瘤激酶（ALK）组成的杂合蛋白的表达，该杂合蛋白表现出不受调节的酪氨酸激酶活性。我们之前已经确定PLC-γ是NPM-ALK的关键下游信号分子，有助于其促有丝分裂潜力。在这里，我们发现NPM-ALK募集磷脂酰肌醇3-激酶（PI 3-激酶）p85亚基的C-末端SH 2结构域，PI 3-激酶测定显示该激酶在体内被NPM-ALK激活，进而激活NPM-ALK表达细胞中的PKB/Akt。使用2种特异性PI 3-激酶抑制剂渥曼青霉素和LY 294002证明了NPM-ALK转化细胞系以及从ALCL患者中建立的细胞系生长需要PI 3-激酶，用NPM-ALK逆转录病毒转导的原代小鼠骨髓显示了PI 3-激酶抑制剂治疗后可逆的转化表型。流式细胞仪分析显示，渥曼青霉素处理的NPM-ALK转化细胞系发生了凋亡，而且，NPM-ALK的过表达可部分阻断促凋亡分子Bad诱导的凋亡，因此，NPM-ALK激活了抗凋亡PI 3-激酶/Akt通路，这可能参与了ALCL的分子发病机制。
More than half of anaplastic large-cell lymphomas (ALCLs) have a chromosomal translocation t(2;5) that leads to the expression of a hybrid protein composed of the nucleolar phosphoprotein nucleophosmin (NPM) and the anaplastic lymphoma kinase (ALK) that exhibits an unregulated tyrosine kinase activity. We have previously identified PLC-gamma as a crucial downstream signaling molecule of NPM-ALK that contributes to its mitogenic potential. Here, we show that NPM-ALK recruits the C-terminal SH2 domain of the phosphatidylinositol 3-kinase (PI 3-kinase) p85 subunit, PI 3-kinase assays revealed that the kinase is activated by NPM-ALK in vivo, in turn activating PKB/Akt in NPM-ALK-expressing cells. The use of 2 specific PI 3-kinase inhibitors, wortmannin and LY294002, demonstrated the requirement of PI 3-kinase for the growth of NPM-ALK-transformed cell lines, as well as a cell line established from a patient with ALCL, Primary murine bone marrow retrovirally transduced with NPM-ALK showed a transformed phenotype that was reversible on treatment with PI 3-kinase inhibitors. Flow cytometric analysis revealed that wortmannin-treated NPM-ALK-transformed cell lines underwent apoptosis, Furthermore, apoptosis induced by overexpression of the pro-apoptotic molecule Bad could be partially blocked by the overexpression of NPM-ALK, Thus, NPM-ALK activates the antiapoptotic PI 3-kinase/Akt pathway, which likely contributes to the molecular pathogenesis of ALCL.