In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells

Abstract

Due to its relatively slow clinical progression, B cell chronic lymphocytic leukemia (B-CLL) is classically described as a disease of accumulation rather than proliferation. However, evidence for various forms of clonal evolution suggests that B-CLL clones may be more dynamic than previously assumed. We used a nonradioactive, stable isotopic labeling method to measure B-CLL cell kinetics in vivo. Nineteen patients drank an aliquot of deuterated water ( 2 H 2 O) daily for 84 days, and 2 H incorporation into the deoxyribose moiety of DNA of newly divided B-CLL cells was measured by gas chromatography/mass spectrometry, during and after the labeling period. Birth rates were calculated from the kinetic profiles. Death rates were defined as the difference between calculated birth and growth rates. These analyses demonstrated that the leukemic cells of each patient had definable and often substantial birth rates, varying from 0.1% to greater than 1.0% of the entire clone per day. Those patients with birth rates greater than 0.35% per day were much more likely to exhibit active or to develop progressive disease than those with lower birth rates Thus, B-CLL is not a static disease that results simply from accumulation of long-lived lymphocytes. Rather, it is a dynamic process composed also of cells that proliferate and die, often at appreciable levels. The extent to which this turnover occurs has not been previously appreciated. A correlation between birth rates and disease activity and progression appears to exist, which may help identify patients at risk for worsening disease in advance of clinical deterioration.

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.…”

Targeting proliferation of chronic lymphocytic leukemia (CLL) cells through KCa3.1 blockade

“…7 While their majority in the peripheral blood is cell cycle arrested, CLL cells in lymphoid organs proliferate, delivering substantial amounts of tumor cells daily. 8 Critically, CLL cells in lymphoid niches are protected against cytotoxic effects of many chemotherapeutics and likely cause minimal residual disease and future relapse. 6 If leukemic cell proliferation is driven by K þ efflux, selective K þ channel blockers could be of clinical benefit to attack B cell neoplasms.…”

Phenotype and immune function of lymph node and peripheral blood CLL cells are linked to transendothelial migration

“…However, in vivo studies of tumor kinetics, using deuterated water, revealed higher than expected tumor cell turnover, with a birth rate of up to 2% per day. 2 The proliferative component of CLL appears to be confined to pseudofollicles or proliferation centers in secondary lymphoid tissues, 3,4 where interactions with non-neoplastic T cells 5,6 and follicular dendritic cells 7 take place, and promote tumor cell growth. 4 In contrast, very few CLL cells in the peripheral circulation show features of proliferation and those that do are believed to represent recent emigrants from the LN.…”