人Toll样受体4内源性配体HSPB8的抗白血病免疫作用研究

项目名称： 人Toll样受体4内源性配体HSPB8的抗白血病免疫作用研究

项目编号： No.30872983

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 马小彤

作者单位： 中国医学科学院

项目金额： 30万元

中文摘要： HSPB8（又称HSP22）参与调节细胞的增殖、凋亡。以往有关HSPB8与肿瘤关系的研究多集中于实体瘤。项目首次发现所有被检测的白血病细胞均无HSPB8表达。由于HSPB8属于热休克蛋白，对应激反应敏感，我们采用热休克、药物处理等多种方法，证实只有去甲基化药物地西他滨能诱导HSPB8表达，且呈剂量依赖。进一步研究发现，白血病细胞HSPB8基因的启动子区呈现甲基化状态。地西他滨处理可逆转白血病细胞甲基化。在慢性粒细胞白血病细胞系K562和淋巴瘤细胞系Namalwa中过表达HSPB8，可显著抑制 K562 和 Namalwa细胞集落形成，Namalwa细胞体外生长，以及K562细胞在裸鼠体内成瘤。过表达HSPB8基因还能增加慢性粒细胞白血病治疗药物伊马替尼诱导的K562细胞凋亡。上述研究首次揭示，在血液系统中，启动子区甲基化是HSPB8不表达的原因，去甲基化药物地西他滨能够诱导HSPB8的表达。过表达HSPB8具有抗白血病作用，并可增强慢性粒细胞白血病对伊马替尼的敏感性，为探索新的白血病治疗策略奠定基础。

中文关键词： HSPB8;地西他滨;伊马替尼; 凋亡;白血病

英文摘要： HSPB8 (also named HSP22) has been shown to be involved in regulation of cell proliferation and apoptosis, and it has also been found to have divergent properties in solid tumors. The purpose of this study was to investigate the expression and function of HSPB8 in hematopoietic malignancies. We found that expression of HSPB8 was absent in hematopoietic tumor cell lines and primary patient and normal volunteer samples. Promoter DNA methylation of HSPB8 was observed in these cells. HSPB8 expression could be restored after demethylation treatment with 5-aza-2'-deoxycytidine (5Aza-dC). Overexpression of HSPB8 reduced colony formation of both K562 and Namalwa cell lines, inhibited the cell growth of Namalwa in vitro and suppressed tumor formation of K562 cells in vivo, and increased imatinib mesylate-induced apoptosis. The present study demonstrates that HSPB8 is silenced by DNA methylation in hematopoietic malignant and normal cells and its expression can be induced by treatment with 5Aza-dC. Overexpression of HSPB8 may have an antitumor activity in chronic myelogenous leukemia and lymphoma and enhance the sensitivity of CML cell line to imatinib. The study provide theoretical basis for choosing more efficacious therapy for CML.

英文关键词： HSPB8;5-aza-2'-deoxycytidine;imatinib mesylate; apoptosis;leukemia