我们对11例弥漫性大B细胞淋巴瘤（DLBCL）患者的瘤组织及正常外周血样品进行全外显子测序，发现其中KDM6B基因存在较高的突变率。该基因编码的去甲基化酶可以通过调节基因的甲基化水平影响相关基因表达，但是目前KDM6B突变在DLBCL发生发展过程中的分子调控机制尚不明确。前期工作结果显示KDM6B的突变可能通过影响下游靶基因的甲基化水平，从而影响DLBCL的发生发展。本课题主要研究：1）通过Sanger法测序，大样本验证KDM6B突变体广泛存在于DLBCL中；2）明确KDM6B突变在DLBCL的增殖、凋亡过程中的作用及其相关的分子机制；3）针对KDM6B突变基因设计小分子化合物，探讨其对KDM6B的功能影响及在DLBCL动物模型中的潜在治疗应用。本课题通过研究KDM6B突变对DLBCL发生发展的调控机制及其小分子化合物的靶向干扰，为DLBCL发病机制提供理论依据，为其临床治疗提供潜在的靶点

Our previous results of whole-exome sequencing of 11 diffuse large B cell lymphoma (DLBCL) samples and their relevant blood samples indicated that there is high frequency mutations existed in KDM6B gene. KDM6B gene encodes a demethylase that regulates histone demethylation, and further modify downstream genes expression. However, the molecular mechanisms of KDM6B gene regulation in DLBCL is not clear. Our previous study indicated that KDM6B was involved in the tumor occurence and development of DLBCL via regulating methylation levels of downstream target genes. Our major strategies are: 1) verify the prevelance of KDM6B mutations using massive DLBCL samples by Sanger sequencing; 2) study the insight into mechanisms of KDM6B gene and its mutants in tumor occurence and development of DLBCL, especially in the procss of cell proliferation and apoptosis; 3) design a series of specific small molecular inhibitors based on possible mutation sites of KDM6B gene, thereafter demonstrate their molecular mechanisms and potentially therapeutic application in in vivo and in vitro. This undergoing project will demonstrate a paradigm in regards to gene mutation and signaling pathway, moreover, the clinical application by using small molecule inhibitors for DLBCL.