布鲁顿酪氨酸激酶（BTK）是BCR信号通路中的关键激酶，BTK抑制剂ibrutinib是B-NHL治疗的新靶向药物。然而在临床研究及与合作方研发新型BTK抑制剂过程中我们发现，并非所有B-NHL患者皆受益，前期基础研究结果也证明不同B-NHL细胞株对ibrutinib的敏感性不同，部分原代B-NHL细胞对ibrutinib也无应答，其中BTK及其相关基因突变是影响ibrutinib疗效的重要因素，申请人在前一国家自然科学基金项目中已经证明Stat3基因突变是影响弥漫大B细胞淋巴瘤疗效的重要因素。本项目将以BTK抑制剂治疗的B-NHL患者为研究对象，利用二代测序中目标区域捕获测序技术及Sanger测序，筛查验证耐药患者肿瘤组织中BTK与Stat3突变位点，并进行功能解析，寻找有效预测BTK抑制剂疗效的标志物，为BTK抑制剂个体化分层治疗提供依据。

Bruton’s tyrosine kinase(BTK)play a key role in the BCR signaling pathway and is a promising therapeutic target in B-NHL. Ibrutinib is a new drug to target and inactivate BTK. However, in clinical trials, we found not all patients responded to ibrutinib. We also found that some cell lines of B-NHL were insensitive to BTK inhibitors. Studies showed that mutations of BTK and other related genes might account for ibrutinib resistance. In our prior project, we found Stat3 mutation play a key role in drug-resistance of B-NHL. Several clinical trials of BTK inhibitors are being performed in our department. In this study, we will screen and perform functional analysis of mutations of BTK and Stat3 in B-NHL patients who are insensitive to ibrutinib. The aim of this study is to find the predicting markers of ibrutinib efficacy, which should have great significance in individualized therapy of BTK inhibitor in B-NHL patients.