Cell proliferation and death: Forgotten features of chronic lymphocytic leukemia B cells

Chronic lymphocytic leukemia (CLL) results from an accumulation of abnormal B cells due to an imbalance between birth and death rates such that the former exceeds the latter. This imbalance can occur as a result of increased birth, decreased death, or a combination of the two. CLL has long been considered a disease in which cell accumulation results from decreased death, due to a genetic defect, with minimal birth of the leukemic clone. This view was promulgated when experimental options were limited and observations in vivo and in vitro were less precise–e.g. CLL cells appeared as resting lymphocytes by light microscopy and responded poorly to mitogens (primarily T-cell mitogens)–at a time when T- and B-cell discrimination was not well appreciated. However, recent studies using more sophisticated measures suggest that the initial characterization of CLL biology needs re-evaluation. Using a safe, non-radioactive in-vivo labeling method that permits the determination of CLL-cell birth rates, we have directly documented that a small fraction of the clone (∼0.1–1.75%), i.e., between ∼1 × 109 and 1 × 1012 cells are born each day in all patients studied. With this value, we calculated death rates of between 0 and 1 × 1012 per day of leukemic cells from individual patients. Thus the dynamic interplay between birth and death that characterizes other leukemias and lymphomas applies to CLL. Therefore, CLL is a disease of both proliferation and accumulation in which a homeostatic balance exists in patients with stable lymphocyte counts or an imbalance exists in patients with rising lymphocyte counts.