Reduction of B cell turnover in chronic lymphocytic leukaemia

Abstract

SummaryWhether chronic lymphocytic leukaemia (CLL) is a latent or a proliferating disease has been intensively debated. Whilst the dogma that CLL results from accumulation of dormant lymphocytes is supported by the unresponsiveness of leukaemic cells to antigens and polyclonal activators, recent in vivo kinetic measurements indicate that B lymphocytes do divide at significant rates in CLL. However, an important and still unanswered question is whether CLL cells proliferate faster or slower compared with their normal counterparts. This report addressed directly this point and compared B-cell kinetics in CLL subjects and healthy controls, using a pulse-chase approach based on incorporation of deuterium from 6,6-2 H 2 -glucose into DNA. We confirmed that B cells proliferated at significant levels in CLL but found that the proliferation rates were reduced compared with healthy subjects (mean 0AE47 vs. 1AE31%/d respectively, P = 0AE007), equivalent to an extended doubling time of circulating B cells (147 d vs. 53 d). In conclusion, CLL B cells proliferate at reduced levels compared with healthy controls. CLL is thus characterized by an aberrant B-cell kinetics with a decrease in cell turnover, an observation that may impact on elaboration of efficient therapeutic strategies.

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).…”

Chronic Lymphocytic Leukemia Cells in a Lymph Node Microenvironment Depict Molecular Signature Associated with an Aggressive Disease

“…CLL is a disease of long-lived B cells that are capable of proliferating upon appropriate stimuli and accumulate in the peripheral blood (PB), bone marrow (BM) and lymph nodes (LNs) (1)(2)(3)(4). There is emerging evidence that the tumor microenvironment influences the survival and drug resistance of CLL cells (5) and other cancer cells (6,7), playing a critical role in the growth, invasion and progression of a variety of malignancies, including hematological malignancies.…”

Measurement of Ribosomal RNA Turnover In Vivo by Use of Deuterium-Labeled Glucose

“…The genomic DNA synthesis rate therefore represents a surrogate for proliferation, a property that has been exploited in recently described methods for measuring cell proliferation using stable (nonradioactive) isotope labeling in vivo in humans (10 -14 ). Applications include the measurement of lymphocyte kinetics in HIV and HTLV-I infection, malignant cell proliferation in leukemia, and vascular smooth muscle in atheroma formation (15)(16)(17)(18)(19)(20).…”