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 (approximately 0.1-1.75%), i.e., between approximately 1x10(9) and 1x10(12) cells are born each day in all patients studied. With this value, we calculated death rates of between 0 and 1x10(12) 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.