目前，DNA 甲基化在 IgM 单克隆丙种球蛋白病谱中的作用仍知之甚少。在本研究中，对 34 名受试者 [23 名 WM、6 名 IgM-MGUS、5 名正常对照] 进行了整合 DNA 甲基化、RNA-seq 和 WES 数据的多组学前瞻性分析。分析的重点是确定 IgM 丙种球蛋白病 (WM/IgM-MGUS) 与对照之间的差异，特别是 WM 和 IgM-MGUS 之间的差异。在各组之间，全基因组 DNA 甲基化分析表明存在大量差异甲基化区域，这些区域根据基因组区域进行注释。接下来，对 RNA-seq 数据进行整合，以确定潜在的表观遗传失调途径。我们发现涉及细胞周期、代谢、细胞因子/免疫信号、细胞骨架、肿瘤微环境和细胞内信号传导的途径被差异激活并可能受到表观遗传调节。重要的是，与 IgM-MGUS 相比，WM 中 CXCR4 信号通路以及多种白细胞介素（IL-6、IL-8、IL15）信号通路呈正富集。对已知肿瘤抑制基因和癌基因的进一步评估发现了几个靶标的差异启动子甲基化以及基因表达的一致变化，包括 CCND1 和 CD79B。总体而言，本报告定义了 IgM 丙种球蛋白病中的异常 DNA 甲基化如何在肿瘤发生和关键细胞功能的表观遗传控制中发挥关键作用。版权所有 © 2024 美国血液学会。

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 defines how aberrant DNA methylation in IgM-gammopathies may play a critical role in the epigenetic control of oncogenesis and key cellular functions.Copyright © 2024 American Society of Hematology.