Progressive de novo DNA methylation at the bcr-abl locus in the course of chronic myelogenous leukemia.
Progressive de novo DNA methylation at the bcr-abl locus in the course of chronic myelogenous leukemia.
复制标题
慢性粒细胞白血病过程中 bcr-abl 位点进行性 DNA 从头甲基化。
DOI：
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发表时间：
1994
影响因子：
11.1
通讯作者：
Y. Ben
中科院分区：
文献类型：
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作者：
M. Zion;Dina Ben;A. Avraham;Ofer Cohen;M. Wetzler;Danielle Melloul;Y. Ben
CpG岛的从头甲基化在哺乳动物细胞中是罕见的事件。它已经在发育过程中观察到，如X染色体失活和基因组印记。DNA甲基化是基因表达表观遗传调控的重要因素，也可能参与肿瘤的发生。在t（9; 22）染色体易位和费城染色体的产生，慢性髓细胞性白血病（CML）的起始事件，大多数abl编码序列融合到bcr基因的5'区。因此，bcr-abl杂合基因的表达受bcr启动子调控。在大多数CML病例中，两个abl启动子之一（Pa）嵌套在bcr-abl转录单位内，应该能够转录来自费城染色体的Ia型6-kb正常abl mRNA。然而，我们已经发现，6 kb的转录本只存在于CML细胞系中含有一个正常的abl等位基因和明显失活的巢式Pa启动子与等位基因特异性甲基化。此外，我们已经注意到Pa启动子包含在CpG岛内，并且在疾病过程中经历进行性从头甲基化。这可以通过以下事实得到证明：在诊断时无甲基化的CML患者的DNA样品在晚期CML中总是甲基化。由于CML中的肿瘤进展不能总是从临床表现中推断，因此从头CpG甲基化的评估可能被证明在疾病的管理中具有关键价值。它可能预示着在骨髓移植（CML唯一潜在的治愈性治疗方法）仍然有效的阶段发生急变。
De novo methylation of CpG islands is a rare event in mammalian cells. It has been observed in the course of developmental processes, such as X chromosome inactivation and genomic imprinting. The methylation of DNA, an important factor in the epigenetic control of gene expression, may also be involved in tumorigenesis. After the t(9;22) chromosomal translocation and generation of the Philadelphia chromosome, the initiating event in chronic myelogenous leukemia (CML), most of the abl coding sequence is fused to the 5' region of the bcr gene. Expression of the hybrid bcr-abl gene is, therefore, regulated by the bcr promoter. In most cases of CML, one of the two abl promoters (Pa) is nested within the bcr-abl transcriptional unit and should be able to transcribe the type Ia 6-kb normal abl mRNA from the Philadelphia chromosome. However, we have found that the 6-kb transcript is present only in CML cell lines containing a normal abl allele and that the apparent inactivation of the nested Pa promoter is associated with allele-specific methylation. Furthermore, we have noticed that the Pa promoter is contained within a CpG island and undergoes progressive de novo methylation in the course of the disease. This is attested to by the fact that DNA samples from CML patients that are methylation-free at the time of diagnosis invariably become methylated in advanced CML. Since tumor progression in CML cannot always be inferred from the clinical presentation, assessment of de novo CpG methylation may prove to be of critical value in management of the disease. It could herald blastic transformation at a stage when bone marrow transplantation, the only potentially curative therapeutic procedure in CML, is still effective.