Multiomics analysis of IgM monoclonal gammopathies reveals epigenetic influence on oncogenesis via DNA methylation

• Published in: Blood Vol. 144; no. 12; pp. 1284 - 1289
• Main Authors: Chohan, Karan, Paludo, Jonas, Dasari, Surendra, Mondello, Patrizia, Novak, Joseph P., Abeykoon, Jithma P., Wenzl, Kerstin, Yang, Zhi-Zhang, Jalali, Shahrzad, Bhardwaj, Vaishali, Krull, Jordan E., Braggio, Esteban, Manske, Michelle K., Paulus, Aneel, Reeder, Craig B., Ailawadhi, Sikander, Chanan-Khan, Asher, Kapoor, Prashant, Kyle, Robert A., Gertz, Morie A., Novak, Anne J., Ansell, Stephen M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.09.2024
• Subjects: Aged; Carcinogenesis - genetics; DNA Methylation; Epigenesis, Genetic; Female; Humans; Immunoglobulin M - genetics; Male; Middle Aged; Monoclonal Gammopathy of Undetermined Significance - genetics; Monoclonal Gammopathy of Undetermined Significance - metabolism; Monoclonal Gammopathy of Undetermined Significance - pathology; Multiomics; Paraproteinemias - genetics; Prospective Studies; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Signal Transduction - genetics; Waldenstrom Macroglobulinemia - genetics; Waldenstrom Macroglobulinemia - immunology
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2023023639

•Global DNA methylation analysis reveals significant DMRs comparing WM with IgM-MGUS and IgM gammopathies with controls across genomic regions.•Epigenetic influence on cellular pathways, including cell signaling and inflammatory response pathways, was observed. [Display omitted] Currently, the role of DNA methylation in the immunoglobulin M (IgM) monoclonal gammopathy disease spectrum remains poorly understood. In the present study, a multiomics prospective analysis was conducted integrating DNA methylation, RNA sequencing (RNA-seq), and whole-exome sequencing data in 34 subjects (23 with Waldenström macroglobulinemia [WM], 6 with IgM monoclonal gammopathy of undetermined significance [MGUS], and 5 normal controls). Analysis was focused on defining differences between IgM gammopathies (WM/IgM-MGUS) compared with controls, and specifically between WM and IgM-MGUS. Between groups, genome-wide DNA methylation analysis demonstrated a significant number of differentially methylated regions that 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 the CXCR4 signaling pathway along with several interleukin (interleukin 6 [IL-6], IL-8, and IL-15) signaling pathways in WM compared with 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. The pathogenesis of Waldenström macroglobulinemia (WM) is unknown. Chohan and colleagues report on multiomic comparative analyses (DNA methylation, whole exome, and RNA sequencing) of WM, IgM monoclonal gammopathy of undetermined significance (MGUS), and normal controls, identifying distinct patterns of transcriptional and epigenetic regulation associated with WM rather than MGUS. The authors’ data highlight the importance of epigenetic influence on cell signaling and inflammation-response pathways that differs between these entities.