早幼粒细胞白血病蛋白PML调节TET2在肿瘤发生发展中的作用及机制

项目名称： 早幼粒细胞白血病蛋白PML调节TET2在肿瘤发生发展中的作用及机制

项目编号： No.31471328

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 杨庆凯

作者单位： 大连医科大学

项目金额： 90万元

中文摘要： 恶性肿瘤中DNA修饰异常是生命科学研究最大热点之一。而甲基胞嘧啶双加氧酶TET2在DNA修饰异常中起到重要作用，但其功能和调控机制尚待研究。申请人前期研究发现早幼粒细胞白血病蛋白PML被有丝分裂原活化蛋白激酶BMK1信号通路调节（Cancer Cell，2010），进而控制肿瘤耐药（Oncogene，2013）。而预实验表明野生型PML，而非突变体PML-RARa，结合并调节TET2。据此，申请人认为PML通过调节TET2，控制表观修饰，参与肿瘤发生发展。本研究拟利用下一代测序、基因敲除细胞和小鼠等手段，通过观察砷化剂等处理下TET2、PML及PML-RARa的分布和细胞生长特征，结合小鼠发病情况，研究PML调节TET2在肿瘤发生发展中的作用；并通过构建表观基因组图谱、表达检测和功能分析，进一步探讨其分子机制和作用靶点。本研究将为阐明DNA表观修饰异常促进肿瘤发生发展的机制奠定基础。

中文关键词： 信号转导通路；早幼粒细胞白血病蛋白；分子机制

英文摘要： Deregulation of the DNA epigenetic modification in cancer is one of the research hot spots. Although growing evidence indicates that aberrant TET-mediated DNA modification plays an important role in tumor, the regulatory mechanism and role still remain elusive. Our previous study indicated that PML is regulated by BMK1 cellular signal transduction pathway (Cancer Cell，2010) and involved in the drug resistance (Oncogene，2013). Our pilot experiment indicated that PML WT significantly regulates TET2, while the PML oncogenic mutant--PML-RARa, interacts with TET2 poorly. Based on these, it is hypothesized that PML regulates the epigenetic modification through the recruitment of TET2, while the deregulation of interaction between PML and TET2 plays an important role in tumorigenesis and tumor progression. In this study, NGS (Next generation sequencing), Cas9-mediated knock out cell and mouse model will be carried out. After the specific treatment (such as arsenic trioxide), the subcellular localization and colocalization of TET2, PML and PML-RARa will be investigated to evaluate the role of PML and TET2 in tumorigenesis and tumor progression. Cas9-mediated knock out cell and mouse model will also be applied to verify the role of PML and TET2. Furthermore, using NGS (Next generation sequencing), the epigenetic map will be built to unveil the regulatory mechanism of TET2. We hope that this study could shed some light on the regulatory mechanism and role of the aberrant DNA epigenetic modification in tumorigenesis and tumor progression.

英文关键词： Signal Transduction Pathway;Promyelocytic Leukemia;Molecular Mechanism