淋巴瘤重现性突变在其发病中起至关重要作用，并可为潜在治疗靶标。目前已在多种淋巴瘤中发现了参与其发生的重现性突变，而在结外NK/T细胞淋巴瘤这一西方罕见、中国高发且疗效差的淋巴瘤中，其重现性突变状况有待深入研究。我们前期通过外显子组及Sanger测序发现该型淋巴瘤中存在多种NF-κB调控及相关信号通路分子的基因突变，其中TNFAIP3是最主要的NF-κB活化调控分子，研究意义最为突出。本项目拟首先增加样本检测TNFAIP3突变类型和发生率；其次在细胞系中通过突变基因表达载体构建、siRNA、EMSA、荧光素酶报告分析、凋亡与增殖活性分析等途径，研究TNFAIP3重现性突变功能及对NF-κB活化的影响与机制；最后结合临床病例，分析此突变与该淋巴瘤组织亚型、放化疗效果及预后的关系，为揭示NK/T细胞淋巴瘤发生及NF-κB组成性活化机制奠定理论基础及提供潜在治疗靶标，为临床疗效及预后评估提供依据。

It has been shown that recurrent mutations play pivotal roles in the pathogenesis of several types of lymphomas, and thus can be potential candidates of molecular therapeutic targets. The incidence of extranodal NK/T cell lymphoma is unusually high in China despite it is very low in the West. Moreover, the therapeutic efficacy is very low. About this specific type of lymphoma-the extranodal NK/T cell lymphoma, little is known on whether recurrent mutations exit and what roles they might play in this disease. Through exome sequencing and Sanger sequencing we have already revealed that there are multiple mutations on molecules that are the key regulatory and related signalling pathways of NF-kappaB. Among these molecules, TNFAIP3 is the “global” inhibitor of NF-kappaB activation. This project proposes firstly to identify the TNFAIP3 recurrent mutations through sequencing in large number of samples. Secondly to investigate the functions of the key TNFAIP3 recurrent mutations and their influence on NF-kappaB activation and its mechanisms, by using the construction of expression vehicle, siRNA, electrophoretic mobility shift assay, NF-kappaB reporter and dual-luciferase assay, apoptosis or proliferation activity analysis. Finally, by analyzing the clinical and experimental data, to reveal how the TNFAIP3 recurrent mutations correlate with subtypes of NK/T cell lymphoma, efficacy of radiotherapy, chemotherapy and the prognosis of this disease. In summary, through identification of TNFAIP3 recurrent mutations and studying their functions, this project designs to study the mechanisms on how extranodal NK/T cell lymphoma occur and how constitutive activation of NF-KappaB signalling pathway affect this disease, aiming to reveal some potential therapeutic targets and provide basis for evaluation of the efficacy and the prognosis of this disease.