CD126 and Targeted Therapy with Tocilizumab in Chronic Lymphocytic Leukemia
CD126 and Targeted Therapy with Tocilizumab in Chronic Lymphocytic Leukemia
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DOI：
10.1158/1078-0432.ccr-15-1139
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发表时间：
2016-05-15
影响因子：
11.5
通讯作者：
Agrawal, Samir G.
中科院分区：
文献类型：
--
作者：
Liu, Feng-Ting;Jia, Li;Agrawal, Samir G.
目的：IL 6通过其膜结合受体（CD 126）和可溶性受体（sCD 126）促进肿瘤生长和信号转导。我们的目的是研究是否在慢性淋巴细胞白血病（CLL）细胞的CD 126表达水平可以预测在体外和体内treatment responsibility.Experimental Design：膜结合的CD 126表达水平测定新鲜分离的CLL B细胞（n = 58），使用流式细胞术。这些CLL细胞与苯丁酸氮芥或氟达拉滨或不与抗CD 126抗体tocilizumab治疗24小时和IL-6介导的STAT 3转录活性和细胞周期的改变进行了evaluated.Results：CD 126表面表达被发现在所有情况下，在体内组成性STAT 3活性的水平呈正相关。CD 126表达水平与CLL细胞对苯丁酸氮芥或氟达拉滨体外治疗的抵抗以及CLL患者体内治疗反应差显著正相关。用抗CD 126抗体tocilizumab阻断IL 6信号传导对STAT 3介导的存活和生长信号有深远的影响：Mcl-1和Bcl-xL减少，有利于凋亡特征; p27减少，细胞周期蛋白E和CDK 2表达增加，导致细胞周期从G 0-G1转变。结论：CD 126高表达的CLL细胞通过IL 6-CD 126-STAT 3轴对化疗药物产生更强的抵抗力。使用托珠单抗阻断CD 126使CLL细胞对化疗敏感。(C)2015年AACR。
Purpose: IL6 promotes tumor growth and signal transduction via both its membrane-bound (CD126) and soluble receptors (sCD126). We aimed to study whether the levels of CD126 expression in chronic lymphocytic leukemic (CLL) cells can predict in vitro and in vivo treatment response.Experimental Design: The levels of membrane-bound CD126 expression were determined on freshly isolated CLL B cells (n = 58) using flow cytometry. These CLL cells were treated with chlorambucil or fludarabine with or without anti-CD126 antibody tocilizumab for 24 hours and IL6-mediated STAT3 transcriptional activity and cell-cycle alteration were evaluated.Results: CD126 surface expression was found in all cases and positively correlated with the levels of in vivo constitutive STAT3 activity. The levels of CD126 expression were significantly and positively correlated with the resistance of CLL cells to in vitro treatment with chlorambucil or fludarabine and poor in vivo treatment response of CLL patients. Blocking IL6 signaling with the anti-CD126 antibody, tocilizumab, had profound effects on STAT3-mediated survival and growth signals: decreased Mcl-1 and Bcl-xL, favoring an apoptotic profile; and decreased p27 with increased cyclin E and CDK2 expression, leading to cell-cycle shift from G0-G1. These tocilizumab-mediated changes induced chemosensitization in resistant CLL cells, with the greatest effect seen in cells with higher CD126 expression (P < 0.001).Conclusions: CLL cells with higher CD126 expression are more resistant to treatment in vivo and in vitro via IL6-CD126-STAT3 axis. Blocking CD126 using tocilizumab sensitizes CLL cells to chemotherapy. (C) 2015 AACR.