The Translational Genomics Research Institute, Phoenix, AZ, USA.
Cancer Res. 2010 Sep 1;70(17):6934-44. doi: 10.1158/0008-5472.CAN-10-0282. Epub 2010 Aug 24.
Multiple myeloma (MM) is a plasma cell malignancy of the bone marrow, which evolves from a premalignant stage called monoclonal gammopathy of undetermined significance (MGUS). In some patients, an intermediate stage referred to as smoldering multiple myeloma (SMM) is clinically recognized, with the full-bore malignancy termed MM. We conducted a study to assess differential CpG methylation at 1,500 genic loci during MM progression and profiled CD138(+) plasma cells from MGUS, SMM, and MM specimens; human myeloma cell lines; and normal plasma cell (NPC) samples. We showed that the number of differentially methylated loci (DML) increased with tumor grade, and the vast majority were due to hypomethylation. Hierarchical clustering analysis revealed samples that coclustered tightly with NPC. These cases, referred to as "normal-like," contained significantly fewer DML when compared with their non-normal-like counterparts and displayed overall methylation levels resembling NPC. This study represents one of the first methylome interrogation studies in MM and points toward global hypomethylation at genic CpG loci as an important and early mechanism driving myelomagenesis. Determining the set of critical genes and pathways based on the myeloma methylome is expected to lead to an improved understanding of biological mechanisms involved in myelomagenesis.
多发性骨髓瘤（MM）是一种骨髓浆细胞恶性肿瘤，由一种称为意义未明的单克隆丙种球蛋白血症（MGUS）的前恶性阶段发展而来。在一些患者中，临床上会识别出一种称为冒烟型多发性骨髓瘤（SMM）的中间阶段，而完全恶性的则称为 MM。我们进行了一项研究，以评估 MM 进展过程中 1500 个基因座的差异 CpG 甲基化，并对 MGUS、SMM 和 MM 标本、人类骨髓瘤细胞系和正常浆细胞（NPC）样本中的 CD138+浆细胞进行了分析。我们表明，差异甲基化位点（DML）的数量随着肿瘤分级的增加而增加，而且绝大多数是由于低甲基化。层次聚类分析显示，与 NPC 紧密聚类的样本。这些被称为“正常样”的病例与非正常样病例相比，DML 明显较少，并且整体甲基化水平类似于 NPC。这项研究是 MM 中第一个全基因组甲基组学研究之一，表明基因 CpG 位点的整体低甲基化是驱动骨髓瘤发生的一个重要和早期的机制。基于骨髓瘤甲基组确定关键基因和途径的集合，有望提高对骨髓瘤发生中涉及的生物学机制的理解。
