靶向MEF2C/HDACs相互作用小分子化合物CC1007抗急性淋巴细胞白血病的效应及机制研究

项目名称： 靶向MEF2C/HDACs相互作用小分子化合物CC1007抗急性淋巴细胞白血病的效应及机制研究

项目编号： No.81470323

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张广森

作者单位： 中南大学

项目金额： 70万元

中文摘要： 急性淋巴细胞白血病(ALL)表现的异质性、易耐药和复发构成了治疗上的挑战。研究显示肌细胞增强因子2C（MEF2C）对T、B-淋巴细胞分化有重要调节作用；MEF2C与IIa型组蛋白去乙酰化酶（HDACs）互作并募集特异转录因子对淋系细胞分化进行调控；ALL病人MEF2C表达失调提示MEF2C/HDACs轴紊乱介导了淋系白血病发病机制。我们前期工作显示CC1007-一种靶向MEF2C/HDACs小分子化合物，能显著抑制T-或B-ALL细胞生长、诱导B-ALL细胞向单核细胞分化。本项目欲深入研究CC1007对原代T-，B-ALL CD34+ 细胞抗白血病作用及机制；确证药物诱导淋系细胞跨系分化现象及机理；探讨cc1007是否卡位在MEF2c/HDACs复合物与转录因子KLF4之间的界面；并在负B-ALL鼠和负T-ALL斑马鱼模型观察药物抗白血病活性，为ALL靶向治疗提供实验依据。

中文关键词： 急性淋巴细胞白血病；肌细胞增强因子2C；组蛋白去乙酰化酶；CC1007；分子靶向

英文摘要： Acute lymphoblastic leukemia（ALL）is an malignant clonal neoplasm origins from lymphoid stem or progenitors, and characterized by high heterogeneity in phenotypes, a poor reaction or resistance to chemotherapies, ease to relapse, and constitutes great challenge on ALL therapy. Recent data have indicated that myocyte enhancer factor 2C(MEF2C)plays an important role on mediating the differentiation and development of T-lymphocytic or B-lymphocytic cells. The interaction of MEF2C with class IIa histone deacetylases(HDACs)contributes to their recruitment to specific transcription factor, which regulates the growth and differentiation of lymphoid cells. It has also been shown that there is dys-expression or mutation of MEF2C gene in ALL patients and suggest aberrant regulation of MEF2C/HDACs axis is involved in the pathogenesis of ALL. Our previous works showed that CC1007, a small molecular compound, which may target to the interaction of MEF2C/HDACs, could inhibit cells proliferation, induces apoptosis significantly both on T-ALL and B-ALL cell lines, and induces B-ALL cells differentiation from lymphoid to monocytic lineage. In the present project, we want to extend the study: (1)To determine the anti-leukemic effect of CC1007 on primary CD34+ leukemia cells from patients with T-ALL or B-ALL, and investigate the change or influence of CC1007 on MEF2C/HDACs gene and proteins; (2)To further confirm the across-lineage differentiation from lymphoid lineage to myeloid lineage and elucidates the regulating mechanism of CC1007 promoting differentiation; (3)To set up human primary B-ALL xenograft NOD/SCID mouse model and suffering T-ALL zebrafish model respectively, and observe the anti-leukemic activity of CC1007 in vivo; (4)To explore whether CC1007 blocks the interaction between MEF2C/HDACs compound and transcription factor KLF4 gene, and uncovers the exact molecular mechanism of CC1007 against ALL. Our results will open up a new path and present an alternative approach for ALL treatment.

英文关键词： acute lymphoblastic leukemia;myocyte enhancer 2C;class IIa histone deacetylases;CC1007;molecular targeting