HCL shows distinct transcriptional and methylation signatures. Integrated methylation (A-B) and gene expression (C-D) profiles of HCL and post-GC B-cell subpopulations (A, methylation; C, gene expression profile) and of HCL and other B-cell tumors (B, methylation; D, gene expression profile). Heat maps show scores from ssGSEA (methylation or GEP). Supervised hierarchical clustering (Euclidean distance, complete linkage) of methylation profiles. The 4 main clusters on the rows comprise processes to be found in HCL with higher methylation and lower gene expression (1. High-M & Dn-Reg) or with lower methylation and higher gene expression (2. Low-M & Up-Reg) or positively correlated for methylation and gene expression (3. Positively correlated) or with no correlation (4. No correlated). fc_met_norm represents fold change in methylation between HCL and postGC B cells, fc_met_tumor represents fold change in methylation between HCL and other B-cell tumors, fc_gep_norm represents fold change in gene expression between HCL and post-GC B cells, and fc_gep_tumor represents fold change in gene expression between HCL and other B-cell tumors. Methylation profiling (histotype_Meth) included HCL, low- and intermediate-maturity memory B cells (loMat_postGC_Bcell and inMat_postGC_Bcell), splenic MGZ B cells (MGZ_Bcell), CLL samples (IGHV3-21⁺ [CLL–VH3-2] and M-CLL and U-CLL IGHV), and SMZL. GEP (histotype_GEP) included HCL, memory B cells (postGC_Bcell), CLL samples (M-CLL and U-CLL IGHV), and SMZL.