Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden.
Am J Hematol. 2012 Apr;87(4):361-7. doi: 10.1002/ajh.23115. Epub 2012 Feb 28.
Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are mature CD5(+) B-cell malignancies with different biological/clinical characteristics. We recently reported an association between different prognostic subgroups of CLL (i.e., IGHV mutated and unmutated) and genomic methylation pattern. However, the relationship between DNA methylation and prognostic markers, such as the proliferation gene expression signature, has not been investigated in MCL. We applied high-resolution methylation microarrays (27,578 CpG sites) to assess the global DNA methylation profiles in 20 MCL (10 each with high/low proliferation signature) and 30 CLL (15 poor-prognostic IGHV unmutated subset #1 and 15 good-prognostic IGHV mutated subset #4) samples. Notably, MCL and each CLL subset displayed distinct genomic methylation profiles. After unsupervised hierarchical clustering, 17/20 MCL cases formed a cluster separate from CLL, while CLL subsets #1 and #4 formed subclusters. Surprisingly, few differentially methylated genes (n = 6) were identified between high vs. low proliferation MCL. In contrast, distinct methylation profiles were demonstrated for MCL and CLL. Importantly, certain functional classes of genes were preferentially methylated in either disease. For instance, developmental genes, in particular homeobox transcription factor genes (e.g., HLXB9, HOXA13), were more highly methylated in MCL, whereas apoptosis-related genes were enriched among targets methylated in CLL (e.g., CYFIP2, NR4A1). Results were validated using pyrosequencing, RQ-PCR and reexpression of specific genes. In summary, the methylation profile of MCL was homogeneous and no correlation with the proliferation signature was observed. Compared to CLL, however, marked differences were discovered such as the preferential methylation of homeobox genes in MCL.
套细胞淋巴瘤（MCL）和慢性淋巴细胞白血病（CLL）是具有不同生物学/临床特征的成熟 CD5（+）B 细胞恶性肿瘤。我们最近报道了 CLL（即 IGHV 突变和未突变）不同预后亚组与基因组甲基化模式之间的关联。然而，MCL 中尚未研究 DNA 甲基化与预后标志物（如增殖基因表达特征）之间的关系。我们应用高分辨率甲基化微阵列（27,578 个 CpG 位点）来评估 20 例 MCL（10 例高/低增殖特征）和 30 例 CLL（15 例预后不良 IGHV 未突变亚组 #1 和 15 例预后良好 IGHV 突变亚组 #4）样本的全基因组 DNA 甲基化谱。值得注意的是，MCL 和每个 CLL 亚组显示出不同的基因组甲基化谱。在无监督层次聚类后，17/20 例 MCL 病例与 CLL 形成一个聚类，而 CLL 亚组 #1 和 #4 形成亚群。令人惊讶的是，在高增殖与低增殖 MCL 之间仅鉴定到 6 个差异甲基化基因（n=6）。相比之下，MCL 和 CLL 之间显示出不同的甲基化谱。重要的是，某些疾病中优先甲基化的基因功能类别。例如，发育基因，特别是同源盒转录因子基因（例如，HLXB9、HOXA13），在 MCL 中甲基化程度更高，而凋亡相关基因在 CLL 中甲基化的靶基因中富集（例如，CYFIP2、NR4A1）。使用焦磷酸测序、RQ-PCR 和特定基因的重新表达对结果进行了验证。总之，MCL 的甲基化谱是同质的，并且未观察到与增殖特征的相关性。然而，与 CLL 相比，发现了明显的差异，例如 MCL 中同源盒基因的优先甲基化。
