CD38 and chronic lymphocytic leukemia: a decade later

Abstract

This review highlights a decade of investigations into the role of CD38 in CLL. CD38 is accepted as a dependable marker of unfavorable prognosis and as an indicator of activation and proliferation of cells when tested. Leukemic clones with higher numbers of CD38(+) cells are more responsive to BCR signaling and are characterized by enhanced migration. In vitro activation through CD38 drives CLL proliferation and chemotaxis via a signaling pathway that includes ZAP-70 and ERK1/2. Finally, CD38 is under a polymorphic transcriptional control after external signals. Consequently, CD38 appears to be a global molecular bridge to the environment, promoting survival/proliferation over apoptosis. Together, this evidence contributes to the current view of CLL as a chronic disease in which the host's microenvironment promotes leukemic cell growth and also controls the sequential acquisition and accumulation of genetic alterations. This view relies on the existence of a set of surface molecules, including CD38, which support proliferation and survival of B cells on their way to and after neoplastic transformation. The second decade of studies on CD38 in CLL will tell if the molecule is an effective target for antibody-mediated therapy in this currently incurable leukemia.

Figures

Figure 1

Structural and functional characteristics of the human CD38 molecule. In human B cells, CD38 is expressed as an integral surface membrane molecule, often in a dimeric conformation. As an enzyme, CD38 may interact with the substrate ligands NAD+ and NADP+, which are converted to cADPR, ADPR, and NAADP, all intracellular Ca2+-mobilizing agents. CD38 also interacts with non-substrate ligands, including CD31 and hyaluronic acid, which regulate cell-cell and cell-matrix contacts. On the plasma membrane, CD38 displays preferential localization in membrane lipid microdomains in close contact with the BCR complex (CD19/CD81) and with molecules regulating homing (CXCR4 and CD49d). CD38 engagement by means of the natural ligand CD31 (or surrogate agonistic mAb) triggers the activation of an intracellular signaling pathway, which includes ZAP-70 and ERK1/2 as major players. These signals increase chemotaxis as well as proliferation of neoplastic B cells. The interplay between the enzymatic and receptor activities still needs to be determined in the CLL context.

Figure 2

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.