WM subgroups show differential TLR/MYD88 pathway activation and histone expression. (A) GSEA comparing MBC-like and PC-like WM patients revealed strong enrichment of the MYD88 neighborhood and CpG stimulation of B cells indicative of enhanced TLR signaling in MBC-like WM. (B) Elevation of MYD88 expression in MBC-like vs PC-like WM patients (P = .024) not observed in normal donor MBC vs PC. (C) Analysis of MBC-like vs PC-like WM subtype-specific gene expression accounting for differences that occur in normal donor MBC/PCs. Scatterplot comparing differential gene expression between normal MBC/PC (x-axis) and WM subtypes (y-axis) of all genes (gray dots). Genes differentially expressed between MBC-like and PC-like WM (fold change >1.5, q < 0.05) are highlighted in red with those that show concordant expression differences between normal donor MBC vs PC in blue. Histone genes showing discordant overexpression in PC-like WM are highlighted. (D) Genomic profile across chromosome 6 in patients showing gain of chr6p. All +6p patients also show loss of 6q. One patient (WM5) with no copy number alterations on chromosome 6 is shown for reference. Histone cluster 1 is gained in all patients with +6p. (E) Expression levels of selected discordantly expressed histone genes in MBC-like and PC-like WM separated by chromosome 6p status. (F) Expression of all histone genes in cluster 1 (n = 49) in PC-like vs MBC-like WM separated by chromosome 6p status. Expression of histone cluster 1 genes in PC-like relative to MBC-like WM patients is significantly elevated relative to all other expressed genes (n = 14 069). P values assessed by Kruskal-Wallis and post hoc Mann-Whitney tests.