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Epigenetic changes during B cell differentiation generates distinct DNA methylation signatures specific for B cell subsets, including memory B cells (MBCs) and plasma cells (PCs). Waldenström's macroglobulinemia (WM) is a complex B cell malignancy uniquely comprised of a mixture of lymphocytic and plasmacytic phenotypes. Here we integrated genome-wide DNA methylation, transcriptome, mutation and other phenotypic features of tumor cells from 35 MYD88-mutated WM patients in relation to normal plasma and B cell subsets. We discovered that WM patients naturally segregate into two groups according to DNA methylation patterns, related to normal MBC and PC profiles, and reminiscent of other memory and plasma cell-derived malignancies. Concurrent analysis of DNA methylation changes in normal and WM development were used to capture tumor-specific events, highlighting a selective reprogramming of enhancer regions in MBC-like WM and repressed and heterochromatic regions in PC-like WM. MBC-like WM hypomethylation was enriched in motifs belonging to PU.1, TCF3 and OCT2 transcription factors and involved elevated MYD88/TLR pathway activity. PC-like WM displayed marked global hypomethylation and selective overexpression of histone genes. Finally, WM subtypes exhibited differential genetic, phenotypic and clinical features. MBC-like WM harbored significantly more clonal CXCR4 mutations (P=0.015), deletion 13q (P=0.006), splenomegaly (P=0.02) and thrombocytopenia (P=0.004), while PC-like WM harbored more deletion 6q (P=0.012), gain 6p (P=0.033), had increased frequencies of IGHV3 genes (P=0.002), CD38 surface expression (P=4.1e-5), and plasmacytic differentiation features (P=0.008). Together our findings illustrate a novel approach to subclassify WM patients using patterns of DNA methylation and reveal divergent molecular signatures among WM patients.

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