Genomic subclassification of WM. It is not clear whether a memory B cell or an activated B cell is the initiating tumor cell in WM, but we do know that it is a post–germinal center cell that has acquired a VDJ_H rearrangement and that expresses surface immunoglobulin M (IgM). This cell usually acquires an MYD88 L265P mutation and may subsequently acquire a CXCR4 WHIM mutation. This is the source of 3 possible genotypes: MYD88^WT, MYD88^L265PCXCR4^WT, and MYD88^L265PCXCR4^WHIM. Although CXCR4 is overexpressed in all cases, the 3 genotypes correspond to 3 different transcriptome profiles (TLR7 overexpression profile, TLR4 overexpression profile, and NF-κB underexpression profile, among others). These 3 genomic and transcriptomic profiles are associated with similar phenotypic cellular and clinical profiles, although they do exhibit important differences, especially from the clinical point of view. SHM, somatic hypermutation; TLR4, Toll-like receptor 4; WT, wild-type.