Figure 3.
WM subtype-specific DNA methylation signatures are shared with other malignancies and highlight candidate deregulated TFs. (A) Global DNA methylation levels in normal and malignant B cells assessed by the average β value on Illumina arrays. Normal B-cell group composed of ncsMBC (n = 6), csMBC (n = 5), PC-tonsil (n = 8), and PC-BM (n = 3); MBC-like WM (n = 14), PC-like WM (n = 18), HP-CLL (n = 39), MM (n = 53). Box represents interquartile range with median, whiskers 2.5% to 97.5% confidence interval. (B) T-distributed stochastic neighbor embedding plot of the 2500 most variable CpGs among normal B cells, WM, HP-CLL, and MM showing unique methylation patterns among normal and malignant cell types. WM more closely associates with HP-CLL than MM. Same sample numbers per group as in panel A. (C) Scatterplots displaying the methylation changes occurring during normal B-cell development (x-axis) with changes occurring in WM tumor cells. Both comparisons use naive B cells (NBCs) as a fixed reference. Mean methylation per cell type of all CpGs assessed by the Illumina arrays are plotted (gray dots). CpGs that demonstrate a methylation loss of >20% beyond the decrease during normal development represent tumor-specific hypomethylation (blue dots). (D) Four-way Venn diagram displaying the overlap of tumor-specific hypomethylated CpGs between WM subtypes along with those in HP-CLL and MM. (E) Enrichment of tumor-specific hypomethylation in genomic regions defined by chromatin states in normal B-cell subsets. Hypomethylation was primarily enriched in enhancer regions in MBC-like WM, whereas was enriched in repressed and quiescent regions in PC-like WM; similar patterns were observed in HP-CLL and MM, respectively. (F) Bubble scatterplots showing the enrichment and prevalence of TF motifs in tumor-specific hypomethylation in MBC-like and PC-like WM. Motifs were determined by de novo motif finding, and motifs present in >2% of regions and P < .05 are displayed. MBC-like WM shows highly prevalent and enriched motifs for POU2F2 (OCT2), TCF3/E2A, and PU.1 (SPI1). (G) Motif logo, consensus match score, and enrichment statistics for highly enriched TF motifs in WM. TSS, transcription start site.

WM subtype-specific DNA methylation signatures are shared with other malignancies and highlight candidate deregulated TFs. (A) Global DNA methylation levels in normal and malignant B cells assessed by the average β value on Illumina arrays. Normal B-cell group composed of ncsMBC (n = 6), csMBC (n = 5), PC-tonsil (n = 8), and PC-BM (n = 3); MBC-like WM (n = 14), PC-like WM (n = 18), HP-CLL (n = 39), MM (n = 53). Box represents interquartile range with median, whiskers 2.5% to 97.5% confidence interval. (B) T-distributed stochastic neighbor embedding plot of the 2500 most variable CpGs among normal B cells, WM, HP-CLL, and MM showing unique methylation patterns among normal and malignant cell types. WM more closely associates with HP-CLL than MM. Same sample numbers per group as in panel A. (C) Scatterplots displaying the methylation changes occurring during normal B-cell development (x-axis) with changes occurring in WM tumor cells. Both comparisons use naive B cells (NBCs) as a fixed reference. Mean methylation per cell type of all CpGs assessed by the Illumina arrays are plotted (gray dots). CpGs that demonstrate a methylation loss of >20% beyond the decrease during normal development represent tumor-specific hypomethylation (blue dots). (D) Four-way Venn diagram displaying the overlap of tumor-specific hypomethylated CpGs between WM subtypes along with those in HP-CLL and MM. (E) Enrichment of tumor-specific hypomethylation in genomic regions defined by chromatin states in normal B-cell subsets. Hypomethylation was primarily enriched in enhancer regions in MBC-like WM, whereas was enriched in repressed and quiescent regions in PC-like WM; similar patterns were observed in HP-CLL and MM, respectively. (F) Bubble scatterplots showing the enrichment and prevalence of TF motifs in tumor-specific hypomethylation in MBC-like and PC-like WM. Motifs were determined by de novo motif finding, and motifs present in >2% of regions and P < .05 are displayed. MBC-like WM shows highly prevalent and enriched motifs for POU2F2 (OCT2), TCF3/E2A, and PU.1 (SPI1). (G) Motif logo, consensus match score, and enrichment statistics for highly enriched TF motifs in WM. TSS, transcription start site.

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