Methylation profiling of Waldenstorm's Macroglobulinemia

Currently, the role of DNA methylation in the IgM-monoclonal gammopathy disease spectrum remains poorly understood. In the present study, a multi-omics prospective analysis was conducted integrating DNA methylation, RNA-seq and WES data in 34 subjects [23 WM, 6 IgM-MGUS, 5 normal controls]. Analysis was focused on defining differences between IgM-gammopathies (WM/IgM-MGUS) compared to controls, and specifically between WM and IgM-MGUS. Between groups, genome-wide DNA methylation analysis demonstrated a significant number of differentially methylated regions which were annotated according to genomic region. Next, integration of RNA-seq data was performed to identify potentially epigenetically deregulated pathways. We found that pathways involved in cell cycle, metabolism, cytokine/immune signaling, cytoskeleton, tumor microenvironment, and intracellular signaling were differentially activated and potentially epigenetically regulated. Importantly, there was a positive enrichment of CXCR4 signaling pathway along with several interleukin (IL-6, IL-8, IL15) signaling pathways in WM compared to IgM-MGUS. Further assessment of known tumor suppressor genes and oncogenes uncovered differential promoter methylation of several targets with concordant change in gene expression, including CCND1 and CD79B. Overall, this report define how aberrant DNA methylation in IgM-gammopathies may play acritical role in the epigenetic control of oncogenesis and key cellular functions.目前，DNA甲基化（DNA methylation）在IgM单克隆丙种球蛋白病谱系中的作用仍不甚明确。本研究纳入34例受试者，包括23例华氏巨球蛋白血症（WM）患者、6例IgM单克隆丙种球蛋白病意义未明型（IgM-MGUS）患者及5名正常对照者，开展了整合DNA甲基化、RNA测序（RNA-seq）及全外显子测序（WES）的多组学前瞻性分析。本分析旨在明确IgM丙种球蛋白病（WM/IgM-MGUS）与正常对照之间的差异，并重点探究WM与IgM-MGUS之间的分子差异。组间全基因组DNA甲基化分析显示，存在大量差异甲基化区域，并根据基因组区域对其完成注释。随后，通过整合RNA-seq数据，筛选出潜在受表观遗传调控异常的通路。研究发现，细胞周期、代谢、细胞因子/免疫信号、细胞骨架、肿瘤微环境及细胞内信号相关通路均存在差异激活，且可能受表观遗传调控。值得注意的是，与IgM-MGUS相比，WM组中C-X-C趋化因子受体4（CXCR4）信号通路及多种白细胞介素（IL-6、IL-8、IL15）信号通路均呈现显著富集。进一步针对已知肿瘤抑制基因及致癌基因的评估发现，多个靶基因的启动子存在差异甲基化，且其基因表达水平亦出现协同改变，包括CCND1与CD79B。综上，本研究阐明了IgM丙种球蛋白病中异常DNA甲基化如何在肿瘤发生及关键细胞功能的表观遗传调控中发挥关键作用。