Characterization of DNA demethylation effects induced by 5-aza-2′-deoxycytidine in patients with myelodysplastic syndrome
Characterization of DNA demethylation effects induced by 5-aza-2′-deoxycytidine in patients with myelodysplastic syndrome
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DOI：
10.1158/0008-5472.can-05-0695
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发表时间：
2005-08-15
期刊：
影响因子：
11.2
通讯作者：
Lyko, F
中科院分区：
文献类型：
--
作者：
Mund, C;Hackanson, B;Lyko, F
氮杂核苷药物如5-氮杂胞苷（Vidaza）和5-氮杂-2 '-脱氧胞苷（地西他滨，Dacogen）在体外作为DNA甲基转移酶抑制剂起作用，并且代表用于治疗骨髓增生异常综合征（MDS）和急性髓性白血病的有前景的新药。在这项研究中，我们旨在确定地西他滨对MDS患者基因组甲基化水平的影响。比较不同的测定建立胶束电动色谱作为一种可靠的方法，用于分析基因组甲基化水平。当用于测定地西他滨治疗不同时间点MDS患者骨髓DNA中的DNA甲基化水平时，结果显示7名患者中有5名患者存在显著（高达70%）的去甲基化。有趣的是，在核型正常化后出现了全基因组去甲基化，这表明非克隆细胞的去甲基化。药物诱导的去甲基化动力学也证实了亚硫酸氢盐测序的近着丝粒卫星元素。我们的结果是第一次显示肿瘤材料中地西他滨的全基因组去甲基化活性。此外，我们的数据揭示了地西他滨介导的去甲基化的新靶点，这对于去甲基化药物治疗方案的改进非常重要。
Azanucleoside drugs such as 5-azacytidine (Vidaza) and 5-aza-2'-deoxycytidine (decitabine, Dacogen) function as DNA methyltransferase inhibitors in vitro and represent promising new drugs for the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia. In this study, we aimed to determine the effect of decitabine on the genomic methylation level in MDS patients. Comparison of different assays established micellar electrokinetic chromatography as a reliable method for the analysis of genomic methylation levels. When used for the determination of DNA methylation levels in bone marrow DNA from MDS patients during various time points of decitabine treatment, the results revealed a significant (up to 70%) demethylation in five of seven patients. Interestingly, genome-wide demethylation appeared after karyotype normalization, which suggests demethylation of nonclonal cells. Drug-induced demethylation dynamics were also confirmed by bisulfite sequencing of pericentromeric satellite elements. Our results are the first to show a genome-wide demethylating activity of decitabine in tumor material. In addition, our data uncovers novel targets of decitabine-mediated demethylation that are important for the refinement of treatment schedules with demethylating drugs.