450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments
450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments
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DOI：
10.1038/leu.2012.245
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发表时间：
2013-01-01
期刊：
影响因子：
11.4
通讯作者：
Rosenquist, R.
中科院分区：
文献类型：
--
作者：
Cahill, N.;Bergh, A-C;Rosenquist, R.
在慢性淋巴细胞白血病（CLL）中，微环境影响基因表达模式；然而，关于甲基化随时间和暴露于特定微环境而变化的程度的知识有限。使用高分辨率450K阵列，我们提供了迄今为止最全面的CLL DNA甲基化研究，分析了来自ighv突变/未治疗和ighv未突变/治疗的配对诊断/随访样本（n = 36）以及患者匹配的外周血和淋巴结样本（n = 20）。在前所未有的规模上，我们发现在ighv突变和未突变的患者之间有2239个差异甲基化的CpG位点，其中大多数位点位于带注释的CpG岛之外。有趣的是，CLL预后基因（如CLLU1、LPL、ZAP70和NOTCH1）、表观遗传调节因子（如HDAC9、HDAC4和DNMT3B）、B细胞信号传导（如IBTK）和许多tgf - β和NF-kappa B/TNF通路基因在亚组之间可选择性地甲基化。相反，随着时间的推移，DNA甲基化被认为是相当稳定的，在亚组中很少有反复发生的变化。尽管随着时间的推移，相对于突变病例，在未突变的ighv中发现了更多的非复发性变化，但这些变化相当于较低的全球变化。同样，在隔室病例之间几乎没有发现变化。总之，我们揭示了CLL亚群显示出独特的甲基化谱，并揭示了甲基化随着时间的推移相对稳定，并且在不同的CLL室中相似，这意味着异常甲基化是早期白血病发生事件。白血病（2013）27,150-158；doi: 10.1038 / leu.2012.245
In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K arrays, we provide the most comprehensive DNA methylation study of CLL to date, analyzing paired diagnostic/follow-up samples from IGHV-mutated/untreated and IGHV-unmutated/treated patients (n = 36) and patient-matched peripheral blood and lymph node samples (n = 20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (for example, CLLU1, LPL, ZAP70 and NOTCH1), epigenetic regulator (for example, HDAC9, HDAC4 and DNMT3B), B-cell signaling (for example, IBTK) and numerous TGF-beta and NF-kappa B/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event. Leukemia (2013) 27, 150-158; doi:10.1038/leu.2012.245