文章：

伊马替尼通过上调DNA甲基转移酶和多梳蛋白引起PTEN基因的表观遗传改变

Imatinib causes epigenetic alterations of PTEN gene via upregulation of DNA methyltransferases and polycomb group proteins

原文发布日期：2011-12-09

DOI: 10.1038/bcj.2011.33

类型: Original Article

开放获取: 是

英文摘要：

We have recently reported the possible imatinib-resistant mechanism; long-term exposure of leukemia cells to imatinib downregulated levels of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) via hypermethylation of its promoter region (Leukemia 2010; 24: 1631). The present study explored the molecular mechanisms by which imatinib caused methylation on the promoter region of this tumor suppressor gene in leukemia cells. Real-time reverse transcription PCR found that long-term exposure of chronic eosinophilic leukemia EOL-1 cells expressing FIP1L1/platelet-derived growth factor receptor-α to imatinib induced expression of DNA methyltransferase 3A (DNMT3A) and histone-methyltransferase enhancer of zeste homolog 2 (EZH2), a family of polycomb group, thereby increasing methylation of the gene. Immunoprecipitation assay found the increased complex formation of DNMT3A and EZH2 proteins in these cells. Moreover, chromatin immunoprecipitation assay showed that amounts of both DNMT3A and EZH2 proteins bound around the promoter region of PTEN gene were increased in EOL-1 cells after exposure to imatinib. Furthermore, we found that levels of DNMT3A and EZH2 were strikingly increased in leukemia cells isolated from individuals with chronic myelogenous leukemia (n=1) and Philadelphia chromosome-positive acute lymphoblastic leukemia (n=2), who relapsed after treatment with imatinib compared with those isolated at their initial presentation. Taken together, imatinib could cause drug-resistance via recruitment of polycomb gene complex to the promoter region of the PTEN and downregulation of this gene's transcripts in leukemia patients.

摘要翻译： 

我们最近报道了可能的伊马替尼耐药机制：白血病细胞长期暴露于伊马替尼会通过其启动子区的高甲基化下调第10号染色体缺失的磷酸酶和张力蛋白同源基因（PTEN）的表达（Leukemia 2010；24：1631）。本研究探讨了伊马替尼诱导白血病细胞中这一抑癌基因启动子区发生甲基化的分子机制。实时逆转录PCR发现，伊马替尼长期作用于表达FIP1L1/血小板衍生生长因子受体-α的慢性嗜酸性白血病EOL-1细胞，可诱导DNA甲基转移酶3A（DNMT3A）及多梳家族成员组蛋白甲基转移酶enhancer of zeste homolog 2（EZH2）的表达，从而增加该基因的甲基化。免疫沉淀实验发现，这些细胞中DNMT3A与EZH2蛋白的复合物形成增多。此外，染色质免疫沉淀实验显示，伊马替尼处理后，EOL-1细胞中结合于PTEN基因启动子区的DNMT3A和EZH2蛋白量均增加。进一步研究发现，与初诊时相比，伊马替尼治疗后复发的慢性髓性白血病（n=1）及费城染色体阳性急性淋巴细胞白血病（n=2）患者分离的白血病细胞中，DNMT3A和EZH2水平显著升高。综上，伊马替尼可通过招募多梳基因复合物至PTEN启动子区并下调该基因转录，导致白血病患者产生耐药性。

原文链接：

Imatinib causes epigenetic alterations of PTEN gene via upregulation of DNA methyltransferases and polycomb group proteins