p15INK4B CPG island methylation in primary acute leukemia is heterogeneous and suggests density as a critical factor for transcriptional silencing
p15INK4B CPG island methylation in primary acute leukemia is heterogeneous and suggests density as a critical factor for transcriptional silencing
复制标题
DOI：
10.1182/blood.v94.7.2445.419k19_2445_2451
复制
发表时间：
1999-10-01
期刊：
影响因子：
20.3
通讯作者：
Herman, JG
中科院分区：
文献类型：
--
作者：
Cameron, EE;Baylin, SB;Herman, JG
细胞周期蛋白依赖性激酶抑制剂p15（INK4B）的启动子区域包含一个CpG岛，该岛在许多血液学恶性肿瘤中被过度甲基化。为了探索甲基化和基因转录模式之间的关系，我们使用了硫酸硫酸盐基因组测序来获得对急性白血病，白血病细胞系和正常淋巴细胞中甲基化的详细分析，P15的整个CPG岛区域很大程度上是甲基化的甲基化甲基化的甲基化甲基化的甲基化，但甲基化的甲基化强度是甲基化的，但甲基化的甲基化剂量是甲基化的。通常在每个样品的等位基因之间保守甲基化密度，但是观察到特定CpG位点甲基化的明显异质性。比较甲基化模式，并用反向转录酶聚合酶链反应（RT-PCR）评估表达。 CPG岛内的甲基化密度，而不是任何特定位置，与转录损失最有效。白血病和甲基化约为每个等位基因上约40％的CpG二核苷酸的甲基化，具有完全的基因沉默，具有变化，但表达降低，密度较少的CpG岛甲基化。我们的结果表明，最好将p15的转录沉默与异常的高甲基化结合使用，最好理解为一种进化过程，涉及逐步增加整个PL5CPG岛的甲基化。 （c）1999年美国血液学学会。
The promoter region of the cyclin-dependent kinase inhibitor p15(INK4B) contains a CpG island that is hypermethylated in many hematologic malignancies. To explore the relationship between patterns of methylation and gene transcription, we used bisulfite genomic sequencing to obtain a detailed analysis of methylation in acute leukemia, leukemia cell lines, and normal lymphocytes, The entire CpG island region of p15 was largely devoid of methylation in normal lymphocytes, but methylation of varying density was found in primary acute leukemia. Methylation density was generally conserved between the alleles from each sample, but marked heterogeneity for the specific CpG sites methylated was observed. Patterns of methylation were compared and expression assessed with reverse-transcriptase polymerase chain reaction (RT-PCR). The density of methylation within the CpG island, and not any specific location, correlates best with transcriptional loss. Leukemias with methylation of approximately 40% of the CpG dinucleotides on each allele had complete gene silencing, with variable, but diminished expression with less dense CpG island methylation. Our results suggest that the transcriptional silencing of p15 in conjunction with aberrant hypermethylation is best understood as an evolutionary process that involves progressively increasing methylation of the entire pl5CpG island. (C) 1999 by The American Society of Hematology.