In vivo Dynamics of Stable Chronic Lymphocytic Leukemia Inversely Correlate with Somatic Hypermutation Levels and Suggest No Major Leukemic Turnover in Bone Marrow

Abstract

Although accumulating evidence indicates that chronic lymphocytic leukemia (CLL) is a disease with appreciable cell dynamics, it remains uncertain whether this also applies to patients with stable disease. In this study, 2 H 2 O was administered to a clinically homogeneous cohort of nine stable, untreated CLL patients. CLL dynamics in blood and bone marrow were determined and compared with normal B-cell dynamics in blood from five healthy individuals who underwent a similar 2 H 2 O labeling protocol. Average CLL turnover rates (0.08-0.35% of the clone per day) were f2-fold lower than average B-cell turnover rates from healthy individuals (0.34-0.89%), whereas the rate at which labeled CLL cells in blood disappeared (0.00-0.39% of B cells per day) was f10-fold lower compared with labeled B cells from healthy individuals (1.57-4.24% per day). Leukemic cell turnover variables inversely correlated with the level of somatic hypermutation of the CLL clone (IgVH mutations). Although CLL cells in bone marrow had a higher level of label enrichment than CLL cells in blood, no difference between proliferation rates and proapoptotic and antiapoptotic profiles of CLL cells from these compartments was observed. These data suggest that, in stable disease, there is a biological relationship between the degree of somatic hypermutation of the CLL clone and its dynamics in vivo. Furthermore, in contrast to lymph nodes, the bone marrow does not seem to be a major CLL proliferation site. [Cancer Res 2008;68(24):10137-44]

Intraclonal Complexity in Chronic Lymphocytic Leukemia: Fractions Enriched in Recently Born/Divided and Older/Quiescent Cells

“…By screening a panel of chemokine receptors expressed on clones from a series of CLL patients (4), we found an inverse relationship between CXCR4 and CD5 densities, with differing shapes among patients ( Figures 1A-D We reasoned that high CD5 density would reflect cellular activation as in normal human B cells (7), and low CXCR4 levels would identify cells that internalized the receptor because of an activation event and thereby passaged from a lymphoid tissue to the periphery (8). As detailed elsewhere (5), incorporation of 2 H into cellular DNA in patients given 2 H 2 O is a direct measure of newly synthesized DNA and hence cell division, thereby allowing study of birth rates of CLL cells in vivo (6,9,10). Therefore, we sorted CLL cells from nine patients consuming at 42 d, Figure 1G; P < 0.0001).…”

Autoantigen can promote progression to a more aggressive TCL1 leukemia by selecting variants with enhanced B-cell receptor signaling

“…These findings are reminiscent of human CL cells that proliferate more actively in LNs and less so in BM and blood, as demonstrated by K i -67 expression (29), deuterium incorporation into newly synthesized DNA in vivo (41,42), and differential expression of activation-associated genes in LNs, BM, and blood (29). Thus, both mouse and human CLL cells divide more actively in secondary lymphoid tissues [spleen and LNs for TCL1-192 (SI Appendix, Fig.…”

Dichotomy in NF-κB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering

“…In a small subset of CLL patients, the disease has a rapid course and requires early treatment. The dynamic cell turnover reported by recent studies (Messmer et al, 2005;van Gent et al, 2008) may well be linked with cell division rates, as well as with the period leukemic cells that reside in LN proliferation centers. Our findings indicate that modeling of the LN characteristics of CLL is feasible and can provide novel information on distinct responses in vitro to cytostatic drugs among prognostic subgroups.…”