Sunday, October 16, 2011

Model of role of CD38

CD38+ CLL cells are more sensitive to chemokine (CXCL12) signals, with a higher likelihood to home to lymphoid tissues than the CD38− cells. Once inside the Lymph Node Proliferation Centers, CLL lymphocytes come into contact with accessory cells, such as nurse-like (NLC), follicular dendritic (FDC), stromal, endothelial, mesenchymal (these may be different names for the same cells in some circumstances), and T cells. The presence of antigen and accessory signals leads to proliferation which runs the risk of causing the acquisition of novel genetic lesions (like del 11q or del 17p) that promote clonal evolution and disease progression. These events are more apparent in the CD38+ subsets.

Other characteristics of the CD38+ and CD38− CLL subgroups are variable telomere lengths, telomerase levels, expression of the COX-2 enzyme, and in vivo incorporation of heavy hydrogen into DNA of dividing leukemic cells. Lastly, they differ in high-risk genomic abnormalities, in the development of new DNA mutations and copy number changes over time.

These findings suggest that cellular proliferation might be at the root of the association between higher levels of CD38, aggressively growing CLL clones, and poor patient outcome. This suggestion is consistent with in vivo labeling experiments using 2H2O (“heavy water”) that demonstrated larger than anticipated rates of CLL birth, especially in patients with poor clinical course and outcome and a several-fold higher percentage of newly born cells in CD38+ fractions of CLL clones than in CD38− counterparts of the same clones.

Furthermore, preliminary results from a large clinical study suggest that the percentage of CD38+ CLL cells strongly correlates with the level of leukemic cell turnover observed in vivo. Finally, a recent study using improved cell surface phenotyping and sorting techniques that incorporate expression densities of CXCR4 and CD5 indicates that the percentage of newly born cells is ∼ 10 times higher in the CD38+ than the CD38− fraction. Thus, the combined kinetic and CXCR4 expression analyses highlight relationships between CD38 expression, in vivo kinetics, cell migration to solid tissues, and clinical outcome.

Therefore, CD38 expression is at least a quantitative reflection of in vivo CLL cell activation. However, the activation status acquired in the PCs of lymphoid tissues may wane over time, leading to the conversion of CD38+ cells to CD38− quiescent cells. The circuit may be restarted when the cells are recruited into lymphoid tissues, where they may be reactivated. The initiating event for this activation is unclear, although the association of higher numbers of CD38+ cells with IGHV unmutated CLL clones that often exhibit biased use and selection for specific IGHV/D/J rearrangements (stereotyped BCRs) suggests that one factor promoting cellular stimulation is BCR signaling.

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