Loss of imprinting at the 14q32 domain is associated with microRNA overexpression in acute promyelocytic leukemia
Loss of imprinting at the 14q32 domain is associated with microRNA overexpression in acute promyelocytic leukemia
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DOI：
10.1182/blood-2012-12-469833
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发表时间：
2014-03-27
期刊：
影响因子：
20.3
通讯作者：
Debernardi, Silvana
中科院分区：
文献类型：
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作者：
Manodoro, Floriana;Marzec, Jacek;Debernardi, Silvana
不同的DNA甲基化模式表征了早幼粒细胞白血病/维甲酸受体-α（PML-RAR α）相关急性早幼粒细胞白血病（APL）的表观遗传景观。我们先前报道了聚集在染色体14 q32上的microRNA（miRNAs）仅在APL中过表达。在这里，使用高通量亚硫酸氢盐测序，我们确定了APL相关的高甲基化在上游差异甲基化区域（DMR），其中还包括增强子阻断蛋白CCCTC结合因子（CTCF）的位点基序。比较诊断/缓解配对患者样本的资料，我们发现APL患者以单等位基因方式获得了高甲基化。DMR的胞嘧啶鸟嘌呤二核苷酸状态与遵循特征性位置依赖模式的miRNA表达相关。此外，在来自已建立的转基因PML-RARA APL小鼠模型的白血病细胞中，在12号染色体的正向区域也检测到高甲基化的特征，包括位于小鼠miRNA簇上游的CTCF结合位点。这些结果，以及该区域在髓系分化过程中不显示DNA甲基化变化的证明，提供了14 q32超甲基化与APL发病机制有关的证据。我们提出了一个模型，其中在14 q32域的印记的损失导致在APL中的miRNA的过表达。
Distinct patterns of DNA methylation characterize the epigenetic landscape of promyelocytic leukemia/retinoic acid receptor-alpha (PML-RAR alpha)-associated acute promyelocytic leukemia (APL). We previously reported that the microRNAs (miRNAs) clustered on chromosome 14q32 are overexpressed only in APL. Here, using high-throughput bisulfite sequencing, we identified an APL-associated hypermethylation at the upstream differentially methylated region (DMR), which also included the site motifs for the enhancer blocking protein CCCTC-binding factor (CTCF). Comparing the profiles of diagnostic/remission paired patient samples, we show that hypermethylation was acquired in APL in a monoallelic manner. The cytosine guanine dinucleotide status of the DMR correlated with expression of the miRNAs following a characteristic position-dependent pattern. Moreover, a signature of hypermethylation was also detected in leukemic cells from an established transgenic PML-RARA APL mouse model at the orthologous region on chromosome 12, including the CTCF binding site located upstream from the mouse miRNA cluster. These results, together with the demonstration that the region does not show DNA methylation changes during myeloid differentiation, provide evidence that 14q32 hypermethylation is implicated in the pathogenesis of APL. We propose a model in which loss of imprinting at the 14q32 domain leads to overexpression of the miRNAs in APL.