Regulation and dysregulation of B lymphopoiesis in mouse bone marrow: in vivo role of macrophage activation (pristane-treatment and malaria-infection), c-myc, c-kit, and immunoglobulin genes

To examine factors influencing normal and disordered genesis of the B lymphocyte lineage in mouse bone marrow, precursor B cell dynamics have been analysed in conditions predisposing to B cell neoplasias and deficiencies. Double immunofluorescence labeling and stathmokinetic techniques have been used to quantitate the population size and mitotic activity of pro-B cells before $ mu$ chain expression, pre-B cells expressing cytoplasmic $ mu$ chains, and B lymphocytes expressing surface IgM. Two conditions associated with prolonged macrophage activation and B cell neoplasia, pristane oil-treatment and malaria infection, have been found to stimulate the proliferation of pro-B cells but to produce increased cell loss at later cell differentiation stages, suggesting that the stimulation of cells undergoing Ig gene rearrangement may predispose to genetic errors leading to cell death or oncogenesis. During a pretumorous period in E$ mu$-myc transgenic mice a marked stimulation of pro-B and pre-B cells is associated with much subsequent cell loss, suggesting that additional mutations are needed to promote B cell survival and the emergence of a tumorigenic clone. Many early precursor B cells express c-kit but their development is not blocked by a neutralizing anti-c-kit antibody in vivo, suggesting that the role of c-kit can be replaced by alternative signalling systems. The introduction of Ig transgenes in scid mutant mice, unable to rearrange endogenous Ig genes, shows that the survival of successive stages in precursor B cell development depends upon the successful progressive expression of the IgM molecule. The work demonstrates that processes influencing both cell proliferation and loss can be critical in regulating the genesis of both normal and potentially neoplastic B cells in the bone marrow