Chronic lymphocytic leukaemia: a disease of activated monoclonal B cells

Abstract

B cell-type chronic lymphocytic leukaemia (CLL) has long been considered a disease of resting lymphocytes. However, cell surface and intracellular phenotypes suggest that most CLL cells are activated cells, although only a small subset progresses beyond the G1 stage of the cell cycle. In addition, traditional teaching says that CLL cells divide rarely, and therefore the build-up of leukaemic cells is due to an inherent defect in cell death. However, in vivo labelling of CLL cells indicates a much more active rate of cell birth than originally estimated, suggesting that CLL is a dynamic disease. Here we review the observations that have led to these altered views of the activation state and proliferative capacities of CLL cells and also provide our interpretation of these observations in light of their potential impact on patients.

Figure 1. CLL clones contain more cells displaying an activated phenotype than CD5⁺ B cells from healthy subjects

After gating on CD19⁺CD5⁺ cells, expression of various surface markers indicative of cellular activation were determined. Only those markers that were expressed significantly more on CLL cells are displayed. From R.N. Damle et al. “B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes”. Blood. 2002; 99: 4087–4093.

Figure 2. Within CLL clones, the numbers of Ki-67⁺ cells increases with the density of CD38 expression

A. After gating on CD19⁺CD5⁺ cells, CD38⁺ cells were divided into 3 fractions (R4, R5, and R6) corresponding to CD38^low, CD38^int, and CD38^high expression. B. Average percentages of Ki-67⁺ cells in the three CD38-density defined subsets. From R.N. Damle et al. “B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes”. Blood. 2002; 99: 4087–4093.

Figure 3. Birth and death rates in CLL patients are reciprocally related

Growth rate trends are indicated across the top. Birth rates (gray bars) and death rates (white bars) are reciprocally related, based on growth rates (top of figure). From B.T. Messmer et al. “In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells”. J Clin Invest 2005; 115: 755–764.

Figure 4. Intraclonal kinetic heterogeneity: within each clone the CD38⁺ fraction is enriched in proliferating cells

After sorting CD19⁺CD5⁺CD3⁻ cells, based on CD38 expression ²H incorporated into DNA was measured by gas chromatography and mass spectrometry. Figure illustrates the average of data from CD38⁺ and CD38- fractions from 12 CLL patients. Notice that the CD38⁺ fraction contains significantly more ²H-labeled DNA during the labeling period, and this equilibrates during washout. Adapted from C. Calissano et al. “In vivo intraclonal and interclonal kinetic heterogeneity in B-cell chronic lymphocytic leukemia”. Blood 2009; 114: 4832–4942.