Differential genome-wide array-based methylation profiles in prognostic subsets of chronic lymphocytic leukemia
Differential genome-wide array-based methylation profiles in prognostic subsets of chronic lymphocytic leukemia
复制标题
DOI：
10.1182/blood-2009-07-232868
复制
发表时间：
2010-01-14
期刊：
影响因子：
20.3
通讯作者：
Rosenquist, Richard
中科院分区：
文献类型：
--
作者：
Kanduri, Meena;Cahill, Nicola;Rosenquist, Richard
全局低甲基化和局部高甲基化是众所周知的癌症表观遗传特征；然而，在慢性淋巴细胞白血病（CLL）中，全基因组表观遗传修饰的研究有限。在这里，我们通过将高分辨率甲基化微阵列（27 578 个 CpG 位点）应用于 23 个 CLL 样本，分析了 CLL 的整体甲基化谱，这些样本属于免疫球蛋白重链变量 (IGHV) 突变（有利）和 IGHV 未突变/IGHV3-21（预后不良）子集。总体而言，结果表明这些亚组之间的甲基化模式存在显着差异。具体来说，在IGHV未突变的CLL中，我们鉴定了7个已知或候选肿瘤抑制基因（例如VHL、ABI3和IGSF4）以及参与细胞增殖和肿瘤进展的8个非甲基化基因（例如分别增强核因子-κB和丝裂原激活蛋白激酶途径的ADORA3和PRF1）的甲基化。相比之下，IGHV 突变患者中的这些基因因甲基化而沉默。使用甲基化特异性聚合酶链式反应、定量逆转录酶-聚合酶链式反应和亚硫酸氢盐测序对选定基因的阵列数据进行验证。最后，通过使用甲基抑制剂 5-aza-2'-deoxycytidine 在 IGHV 未突变样品中重新诱导 4 个甲基化肿瘤抑制基因（例如 VHL 和 ABI3），显示了 DNA 甲基化在调节基因启动子中的重要性。总而言之，我们的数据首次揭示了 CLL 预后子集之间整体甲基化谱的差异，这可能揭示了 CLL 发病机制中涉及的表观遗传沉默机制。 （血。2010；115：296-305）
Global hypomethylation and regional hypermethylation are well-known epigenetic features of cancer; however, in chronic lymphocytic leukemia (CLL), studies on genome-wide epigenetic modifications are limited. Here, we analyzed the global methylation profiles in CLL, by applying high-resolution methylation microarrays (27 578 CpG sites) to 23 CLL samples, belonging to the immunoglobulin heavy-chain variable (IGHV) mutated (favorable) and IGHV unmutated/IGHV3-21 (poor-prognostic) subsets. Overall, results demonstrated significant differences in methylation patterns between these subgroups. Specifically, in IGHV unmutated CLL, we identified methylation of 7 known or candidate tumor suppressor genes (eg, VHL, ABI3, and IGSF4) as well as 8 unmethylated genes involved in cell proliferation and tumor progression (eg, ADORA3 and PRF1 enhancing the nuclear factor-kappa B and mitogen-activated protein kinase pathways, respectively). In contrast, these latter genes were silenced by methylation in IGHV mutated patients. The array data were validated for selected genes using methylation-specific polymerase chain reaction, quantitative reverse transcriptase-polymerase chain reaction, and bisulfite sequencing. Finally, the significance of DNA methylation in regulating gene promoters was shown by reinducing 4 methylated tumor suppressor genes (eg, VHL and ABI3) in IGHV unmutated samples using the methyl-inhibitor 5-aza-2'-deoxycytidine. Taken together, our data for the first time reveal differences in global methylation profiles between prognostic subsets of CLL, which may unfold epigenetic silencing mechanisms involved in CLL pathogenesis. (Blood. 2010; 115:296-305)