Proposed model explaining a role of CD38 in the pathogenesis and progression of CLL. (A) CD38⁺ CLL cells (red) are more sensitive to CXCL12 signals, with a higher propensity to home to lymphoid tissues than the CD38⁻ counterpart (brown). (B) Once inside the LN PCs, CLL lymphocytes come into contact with accessory cells, such as nurse-like (NLC), follicular dendritic (FDC), stromal, endothelial, mesenchymal, and T cells. The presence of antigen and accessory signals leads to proliferation and potentially to acquisition of novel genetic lesions, which promote clonal evolution and disease progression. These events are more apparent in the CD38⁺ subsets. The C > G SNP occurring in a region of CD38 critical for transcriptional regulation adds an additional element of complexity, potentially affecting the levels of CD38 expression after microenvironmental interactions.