DNA methylation changes after 5-aza-2′-deoxycytidine therapy in patients with leukemia
DNA methylation changes after 5-aza-2′-deoxycytidine therapy in patients with leukemia
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DOI：
10.1158/0008-5472.can-05-2385
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发表时间：
2006-05-15
期刊：
影响因子：
11.2
通讯作者：
Issa, Jean-Pierre J.
中科院分区：
文献类型：
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作者：
Yang, Allen S.;Doshi, Ketan D.;Issa, Jean-Pierre J.
5-氮杂-2 '-脱氧胞苷（地西他滨）被认为通过其抑制DNA甲基化的能力在骨髓性白血病中具有临床活性。为了研究这一点，我们检测了接受地西他滨治疗的白血病患者的DNA甲基化。治疗后5天，总基因组5-甲基胞嘧啶/胞嘧啶平均下降了14%（从4.3%到3.7%），而重复DNA元件的甲基化平均下降了9%和16%的Alu和长散布的核苷酸元件，分别。甲基化在5 - 20 mg/m2/d剂量范围内随剂量增加呈线性下降（r = 0.88; P = 0.05），但在此剂量以上出现平台期。低剂量（5-20 mg/m2/d）治疗的急性髓细胞性白血病患者的低甲基化与应答相关，而高剂量（100-180 mg/m2/d）治疗的慢性髓细胞性白血病患者的低甲基化与应答无关。在27%的患者中发现了p15异常甲基化（> 10%），其中80%的患者显示至少减少了三分之一，但这与反应无关。印迹基因H19在地西他滨后甲基化几乎没有变化。总之，我们显示低剂量地西他滨后的剂量依赖性低甲基化。增加剂量，这已被证明在以前的反应率降低，并没有伴随着进一步的低甲基化。
5-Aza-2'-deoxycytidine (decitabine) is postulated to have clinical activity in myeloid leukemias via its ability to inhibit DNA methylation. To study this, we examined DNA methylation in patients with leukemia treated with decitabine. Five days after the treatment, total genomic 5-methylcytosine/ cytosine decreased on average by 14% (from 4.3% to 3.7%), whereas methylation of repetitive DNA elements showed a mean decrease of 9% and 16% for Alu and long interspersed nucleotide elements, respectively. Methylation decreased linearly with increasing doses between 5 and 20 mg/m(2)/d (r = 0.88; P = 0.05) but showed a plateau above that. Hypo-methylation correlated with response in patients with acute myelogenous leukemia treated with low doses (5-20 mg/m(2)/d), but patients with chronic myelogenous leukemia treated with high doses (100-180 mg/m(2)/d) showed no such correlation. Aberrant methylation of p15 (> 10%) was found in 27% of patients, and 80% of these showed a decrease by at least one third, but this did not correlate with response. The imprinted gene H19 showed little change in methylation after decitabine. In conclusion, we show dose-dependent hypomethylation after decitabine at low doses. Increasing the dose, which has been shown previously to result in a reduced response rate, was not accompanied by further hypomethylation.