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首页> 外文期刊>Cell death & disease. >Gefitinib targets ZAP-70-expressing chronic lymphocytic leukemia cells and inhibits B-cell receptor signaling
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Gefitinib targets ZAP-70-expressing chronic lymphocytic leukemia cells and inhibits B-cell receptor signaling

机译：吉非替尼靶向表达ZAP-70的慢性淋巴细胞白血病细胞并抑制B细胞受体信号传导

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Chronic lymphocytic leukemia (CLL) can be divided into groups based on biomarkers of poor prognosis. The expression of the tyrosine kinase ZAP-70 (member of the Syk tyrosine kinase family) in CLL cells is associated with shorter overall survival in CLL patients. Currently, there is a lack of targeted therapies for patients with ZAP-70 expression in CLL cells. The tyrosine kinase inhibitor gefitinib has been shown to be effective at induce apoptosis in acute myeloid leukemia through inhibition of Syk. In this study, we sought to test the efficacy of gefitinib in primary human ZAP-70+ CLL cells. We demonstrate that gefitinib preferentially induces cell death in ZAP-70-expressing CLL cells with a median IC 50 of 4.5 μ M. In addition, gefitinib decreases the viability of ZAP-70+ Jurkat T leukemia cells but fails to affect T cells from CLL patients. Western blot analysis shows gefitinib reduces both basal and B-cell receptor (BCR)-stimulated phosphorylation of Syk/ZAP-70, ERK, and Akt in ZAP-70+ CLL cells. Moreover, gefitinib inhibits the pro-survival response from BCR stimulation and decreases pro-survival proteins such as Mcl-1. Finally, ZAP-70 expression sensitizes Raji cells to gefitinib treatment. These results demonstrate that gefitinib specifically targets ZAP-70+ CLL cells and inhibits the BCR cell survival pathway leading to apoptosis. This represents the likelihood of tyrosine kinase inhibitors being effective targeted treatments for ZAP-70+ CLL cells. Cell Death and Disease (2014) 5, e1439; doi: 10.1038/cddis.2014.391 ; published online 2 October 2014
机译：根据预后不良的生物标志物，可将慢性淋巴细胞性白血病（CLL）分为几类。酪氨酸激酶ZAP-70（Syk酪氨酸激酶家族的成员）在CLL细胞中的表达与CLL患者总体生存期较短有关。当前，缺乏针对CLL细胞中ZAP-70表达的患者的靶向疗法。酪氨酸激酶抑制剂吉非替尼已显示可通过抑制Syk有效诱导急性髓细胞性白血病的细胞凋亡。在这项研究中，我们试图测试吉非替尼在原代人ZAP-70 + CLL细胞中的功效。我们证明吉非替尼优先诱导ZAP-70表达CLL细胞死亡，中位IC 50为4.5μM。此外，吉非替尼降低ZAP-70 + Jurkat T白血病细胞的生存能力，但不会影响CLL的T细胞耐心。蛋白质印迹分析表明，吉非替尼可同时降低ZAP-70 + CLL细胞中Syk / ZAP-70，ERK和Akt的基础和B细胞受体（BCR）刺激的磷酸化。此外，吉非替尼抑制来自BCR刺激的促生存应答，并降低促生存蛋白（例如Mcl-1）。最后，ZAP-70表达使Raji细胞对吉非替尼治疗敏感。这些结果表明，吉非替尼特异性靶向ZAP-70 + CLL细胞并抑制导致凋亡的BCR细胞存活途径。这代表酪氨酸激酶抑制剂成为ZAP-70 + CLL细胞有效靶向治疗的可能性。 Cell Death and Disease（2014）5，e1439; doi：10.1038 / cddis.2014.391; 2014年10月2日在线发布

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