Clinical implications of aberrant DNA methylation patterns in acute myelogenous leukemia
Clinical implications of aberrant DNA methylation patterns in acute myelogenous leukemia
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DOI：
10.1007/s00277-005-0005-0
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发表时间：
2005-12-01
影响因子：
3.5
通讯作者：
Osieka, R
中科院分区：
文献类型：
--
作者：
Galm, O;Wilop, S;Osieka, R
基因启动子区域附近CpG岛的高甲基化与转录失活相关，是肿瘤发生中基因沉默的重要机制。这种表观遗传现象可以与DNA突变和缺失一起破坏肿瘤抑制基因的功能。采用甲基化特异性聚合酶链反应（methylation-specific polymerase chain reaction，PCR）对60例急性髓性白血病（acute myelogenous leukemia，AML）患者的11个肿瘤相关基因启动子相关CpG岛甲基化状态进行了分析。在患者样本中，细胞因子信号传导抑制因子-1的异常甲基化频率为45.0%（27/60），p15的异常甲基化频率为31.7%（19/60），维甲酸受体β 2的异常甲基化频率为20.0%（12/60），p73和E-钙粘蛋白的异常甲基化频率为13.3%（8/60），O-6-甲基鸟嘌呤DNA甲基转移酶的异常甲基化频率为5.0%（3/60），死亡相关蛋白激酶1和hMLH 1为3.3%（2/60），p16为1.7%（1/60），基质金属蛋白酶组织抑制因子3和Ras相关结构域家族1A为0%（0/60）。在所有法裔美国人和英国人的AML亚型和所有细胞遗传学风险组中均发现异常DNA甲基化。在具有不利核型的AML患者中，似乎存在甲基化频率较高的趋势，但这种差异无统计学显著性。我们的数据表明，涉及基本细胞通路的多个基因的超甲基化是AML中的常见事件，其在所检查的基因之间的频率变化很大。影响参与调节细胞周期抑制、细胞粘附、生长因子信号传导和细胞凋亡的基因的表观遗传事件的积累可能促成恶性AML表型。对表观遗传学在癌症相关基因异常沉默中的作用的认识不断增加，为AML中使用去甲基化剂的靶向治疗方法提供了理论基础和分子基础。
Hypermethylation of CpG islands near gene promoter regions is associated with transcriptional inactivation and represents an important mechanism of gene silencing in carcinogenesis. Such epigenetic phenomena can act alongside DNA mutations and deletions to disrupt tumor-suppressor gene function. The methylation status of the promoter-associated CpG islands from 11 well-characterized cancer-related genes was analyzed by methylation-specific polymerase chain reaction in 60 adult patients with acute myelogenous leukemia (AML) at diagnosis. The frequency of aberrant methylation among the patient samples was 45.0% (27/60) for suppressor of cytokine signaling-1, 31.7% (19/60) for p15, 20.0% (12/60) for retinoic acid receptor beta 2, 13.3% (8/60) for p73 and E-cadherin, 5.0% (3/60) for O-6-methylguanine DNA methyltransferase, 3.3% (2/60) for death-associated protein kinase 1 and hMLH1, 1.7% (1/60) for p16, and 0% (0/60) for the tissue inhibitor of matrix metalloproteinases-3 and Ras association domain family 1A. Aberrant DNA methylation was found in AML of all French-American-British subtypes and throughout all cytogenetic risk groups. There appeared to be a trend towards a higher methylation frequency in AML patients with an unfavorable karyotype, but this difference was not statistically significant. Our data indicate that hypermethylation of multiple genes involving fundamental cellular pathways is a common event in AML, which varies greatly in frequency among the genes examined. The accumulation of epigenetic events affecting genes which are involved in regulating cell cycle inhibition, cell adhesion, growth factor signaling, and apoptosis may contribute to the malignant AML phenotype. The growing knowledge of the role of epigenetics in the aberrant silencing of cancer-related genes provides a rationale and molecular basis for targeted therapeutic approaches with demethylating agents in AML.