Acute lymphoblastic leukemia displays a distinct highly methylated genome

DNA methylation is tightly regulated during development and is stably maintained in normal cells. In contrast, the methylome of cancer cells is commonly characterized by a global loss of DNA methylation co-occurring with CpG island hypermethylation. In acute lymphoblastic leukemia (ALL), the commonest childhood cancer, perturbations of CpG methylation have been reported to be associated with genetic disease subtype and outcome, but data examining large cohorts at genome-wide scale are lacking. Here, we performed whole-genome bisulfite sequencing of leukemic cells across multiple subtypes of ALL, leukemia cell lines and normal hematopoietic cells, and show that in contrast to most cancers, ALL samples only exhibit CpG island hypermethylation but minimal global loss of methylation. This was most pronounced in T-ALL and accompanied by an exceptionally broad range of hypermethylation of CpG islands between patients that is influenced by TET2 and DNMT3B. These findings demonstrate that ALL is characterized by an unusually highly methylated genome, and provide insights into the deregulation of methylation in cancer. Overall design: Genome-wide DNA methylation profiling of B-ALL and T-ALL cell lines as well as DNA methylation and expression profiling of Jurkat cells with TET2 knockout.

DNA甲基化（DNA methylation）在发育过程中受到严格调控，并在正常细胞中维持稳定状态。与之相反，癌细胞的甲基化组通常以全基因组DNA甲基化丢失伴随CpG岛（CpG island）高甲基化为典型特征。
作为最常见的儿童恶性肿瘤，急性淋巴细胞白血病（acute lymphoblastic leukemia, ALL）中已有研究报道CpG甲基化紊乱与疾病遗传亚型及预后相关，但目前仍缺乏全基因组层面针对大型队列的相关研究数据。
本研究对覆盖多种ALL亚型的白血病细胞、白血病细胞系及正常造血细胞开展了全基因组亚硫酸氢盐测序（whole-genome bisulfite sequencing），结果显示，与多数癌症不同，ALL样本仅表现出CpG岛高甲基化，而全局甲基化丢失程度极微。
该特征在T细胞急性淋巴细胞白血病（T-ALL）中最为显著，且患者间CpG岛高甲基化范围异常广泛，这一现象受TET2与DNMT3B基因调控。
本研究结果表明，ALL的基因组甲基化水平异常偏高，同时为癌症中甲基化调控紊乱的机制提供了新的见解。
研究设计概况：对B细胞急性淋巴细胞白血病（B-ALL）与T-ALL细胞系进行全基因组DNA甲基化谱分析，同时对TET2基因敲除的Jurkat细胞开展DNA甲基化及表达谱分析。