Apoptosis and its modulation during B lymphopoiesis in mouse bone marrow

Studies in normal. gene-deleted, transgenic and mutant mice have examined a poptotic cell death and its role in B lymphopoiesis in bone marrow Apoptoti c activity has been quantitated among phenotypically defined populations of precursor B cells using flow cytometry of apoptotic cells and an establish ed model of B-cell development. In normal mice, the frequencies of apoptoti c cells (apoptotic index) and accumulation of apoptotic cells during short- term culture (apoptotic rate) are maximal at around the pro/pre-B-cell tran sition and among immature B lymphocytes. The brief period between onset of apoptosis and clearance by macrophages (apoptotic transit time) is similar for most precursor B-cells. Apoptosis-modulating factors produce substantia l changes in apoptotic activity among pro-B and pre-B cells, associated wit h altered expression of bcl-2 family proteins. Pro-B-cell apoptosis, normal ly extensive, is markedly suppressed in the absence of p53. Complete pro-B- cell abortion in RAG-2 deletion provides an assay for apoptotic fractions i n other experimental systems. Pre-B-cell apoptosis is enhanced by deficienc ies of interleukin (IL)-7, Abl protooncogene or colony-stimulating factor ( CSF)-1 and overexpression of heat-stable antigen, and is inhibited by IL-7 and p190(bcr/abl) transgenes. CSF-1 and melatonin administration inhibit pr e-B-cell apoptosis. probably via stromal cell stimulation. Such apoptotic m odulation has implications for B-cell homeostasis. quality control, immunod eficiency and neoplasia.