Identification of aberrantly methylated genes in association with adult T-cell leukemia
Identification of aberrantly methylated genes in association with adult T-cell leukemia
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DOI：
10.1158/0008-5472.can-04-1422
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发表时间：
2004-09-01
期刊：
影响因子：
11.2
通讯作者：
Matsuoka, M
中科院分区：
文献类型：
--
作者：
Yasunaga, J;Taniguchi, Y;Matsuoka, M
在本研究中，我们使用甲基化 CpG 岛扩增/代表性差异分析方法，鉴定了成人 T 细胞白血病 (ATL) 细胞中的 53 个异常高甲基化 DNA 序列。我们还观察到随着疾病进展，这些区域的甲基化密度成比例增加。在高甲基化区域附近发现了七个基因，这些基因在正常 T 细胞中表达，但在 ATL 细胞中受到抑制。在这些沉默基因中，Kruppel样因子4（KLF4）基因是细胞周期调节因子，早期生长反应3（EGR3）基因是诱导Fas配体（FasL）表达的关键转录因子。用 5-aza-2'-deoxycytidine 处理导致其转录恢复，表明它们的沉默可能与 DNA 高甲基化有关。为了研究它们在 ATL 细胞中的功能，我们转染了表达 KLF4 和 EGR3 基因的重组腺病毒载体。 KLF4的表达诱导ATL细胞凋亡，而EGR3的强制表达诱导FasL基因的表达，导致细胞凋亡。因此，抑制EGR3的表达使ATL细胞能够逃避FasL介导的激活诱导的细胞死亡。我们的结果表明，甲基化 CpG 岛扩增/代表性差异分析方法可以分离白血病细胞特有的高甲基化 DNA 区域，从而揭示 DNA 甲基化在白血病发生中的作用。
In this study, we identified 53 aberrantly hypermethylated DNA sequences in adult T-cell leukemia (ATL) cells using methylated CpG island amplification/representational difference analysis method. We also observed a proportionate increase in the methylation density of these regions with disease progression. Seven genes, which were expressed in normal T cells, but suppressed in ATL cells, were identified near the hypermethylated regions. Among these silenced genes, Kruppel-like factor 4 (KLF4) gene is a cell cycle regulator and early growth response 3 (EGR3) gene is a critical transcriptional factor for induction of Fas ligand (FasL) expression. Treatment with 5-aza-2'-deoxycytidine resulted in the recovery of their transcription, indicating that their silencing might be associated with DNA hypermethylation. To study their functions in ATL cells, we transfected recombinant adenovirus vectors expressing KLF4 and EGR3 genes. Expression of KLF4 induced apoptosis of ATL cells whereas enforced expression of EGR3 induced the expression of FasL gene, resulting in apoptosis. Thus, suppressed expression of EGR3 enabled ATL cells to escape from activation-induced cell death mediated by FasL. Our results showed that the methylated CpG island amplification/representational difference analysis method allowed the isolation of hypermethylated DNA regions specific to leukemic cells and thus shed light on the roles of DNA methylation in leukemogenesis.