Remarkable Differences in Cellular Activation State and Migratory and Proliferative Potential among Clonal Cells Derived from Different Tissues of Chronic Lymphocytic Leukemia Patients.

Abstract

An antigen-independent process that takes place in the bone marrow (BM) leads to the birth of B cells from bone marrow precursors. Cross-talk between components of the microenvironment of BM or secondary lymphoid compartment(s), eg. spleen (SP), nurtures the subsequent evolution of B cells and governs in large part the natural history of normal B cells and B cell malignancies including chronic lymphocytic leukemia (B-CLL). Interaction of B cells with stromal elements confers upon them features enabling their transient sequestration, proliferation and extended survival. In this report we have compared the characteristics of clonal B-CLL cells obtained from paired specimens (peripheral blood, PB with corresponding BM or SP obtained within an interval of less than 1 month of each other) from 17 individual untreated B-CLL patients. These cells were tested by surface immunofluorescence and flow cytometry for their expression of a panel of chemokine receptors (CCR −1, −2, −4, and −7 and CXCR−1, −2, −3, and −4) and markers of cellular activation (CD23, CD62L, CD69, CD71 and HLA-DR). The relative age of the B cells (telomere length) and their ability to maintain telomere length (telomerase activity) were studied in paired BM/SP and PB samples from 15 of these cases. Although PB-, BM- and SP-derived B cells expressed activation markers, specifically, the percentages of cells expressing ZAP-70 and Ki-67 were significantly higher in BM- and SP-derived B cells than those expressed by corresponding PB-derived B cells (p<0.01). Increase in extent of CD38-positivity among members of the clone correlates with poor prognosis in B-CLL. Interestingly, in cases with low CD38 expression (<30% cells expressing CD38), the percentage of B-CLL cells expressing CXCR3 and CCR7 was significantly higher among PB-B cells, than BM/SP-derived B cells. No such differences existed in cases with high CD38 expression. This suggests a role for these receptors and their ligands in maintaining homeostasis of B-CLL cells in this subset of cases (that does not show remarkable progression of disease). In each of the 15 cases studied BM and SP-B cells had significantly higher telomerase activity (p<0.01) than those in PB, although telomere lengths of B cells from both sources were comparable. These findings highlight important differences in cellular kinetics among lymphoid compartments in B-CLL.