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.

Assessment of Peripheral Blood and Bone Marrow Cells Apoptosis Caused by Purine Analogues in Patients with Chronic Lymphocytic Leukemia in Correlation with Parameters of Disease Progression

“…In an analysis by Messmer et al [3] it was demonstrated that the leukemic cells of each patient had definable birth rates and those patients with higher birth rates were much more likely to exhibit progressive disease than these with lower birth rates. A correlation between birth rates and disease activity appears to exist that may help to identify patients at risk for worsening disease and in advance of clinical deterioration [3]. The CD38-positive fraction is more active than the CD38-negative counterparts.…”

“…In advanced stage CLL patients, a clone of malignant cells previously arrested in G₀/G 1 may evolve into an actively proliferating population [24]. Cell proliferation and death rates differ considerably among CLL patients, and the level of CLL turnover is important for the natural history of the progression of the disease in an individual patient, which can have significant clinical implications [3,23]. …”

“…Due to its relatively slow clinical progression, CLL is classically described as a disease of accumulation rather than proliferation. However, evidence for various forms of clonal evolution suggests that CLL may be more dynamic than previously assumed, and that proliferation may be an important factor contributing to tumor mass growth [3]. …”

Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice

“…This is an approach our group has previously applied to identify causal pathway BMs in other conditions, such as neurodegeneration (Fanara et al ., 2012), fibrotic disease (Decaris et al ., 2015), and cancer (Messmer et al ., 2005). The concept underlying this strategy is that the activity of a metabolic process is best characterized by the molecular flux rate traversing the pathway and that changes in the flux rates of metabolic processes that play a causal role in the functional alterations of the condition may manifest earlier and more sensitively than static pathologic changes or complex clinical outcomes.…”

Cytokinesis arrest and multiple centrosomes in B cell chronic lymphocytic leukaemia

“…Initially, CLL was considered to result from the accumulation of long‐lived, but resting lymphocytes; however, recent evidence points to the presence of a pool of proliferating B cells 1. Clinically, CLL is a very heterogeneous disease; many patients require no therapy and show an asymptomatic disease, while other patients suffer from a rapidly progressing disease despite treatment.…”