Structural and functional considerations for the role of CD38 in normal and CLL B cells. (A) Structural and functional characteristics of the human CD38 molecule. CD38 is expressed as an integral surface membrane molecule on B lymphocytes, often in a dimeric conformation. Because it is an ectoenzyme, CD38 may interact with the substrate ligands NAD⁺ and NADP⁺, which are converted to the intracellular Ca²⁺-mobilizing agents cADPR, ADPR, and NAADP. CD38 also interacts with nonsubstrate ligands, including CD31 and hyaluronic acid, which regulate cell-cell and cell-matrix contact. CD38 is preferentially localized in membrane lipid microdomains in close contact with the BCR complex (CD19/CD81) and with molecules regulating homing (CXCR4 and CD49d). CD38 engagement by natural (CD31) or surrogate (agonistic mAb) ligands triggers activation of intracellular signaling pathways that include ZAP-70 and ERK1/2 as major players. These signals increase chemotaxis and proliferation of neoplastic B cells. (B) Proposed model explaining a role of CD38 in the pathogenesis and progression of CLL. (Bi) CD38⁺ CLL cells (red) are more sensitive to CXCL12 signals and have a higher propensity to home to lymphoid tissues than their CD38⁻ counterparts (brown). (Bii) Once inside lymph node proliferation centers, CLL cells come into contact with accessory cells such as nurse-like, follicular dendritic, stromal, endothelial, mesenchymal, and T cells. The presence of Ag and accessory signals leads to proliferation and potentially acquisition of novel genetic lesions, promoting clonal evolution and disease progression. These events are more apparent in the CD38⁺ subsets. Used with permission from Malavasi et al.⁴²