B lymphocytes are continually generated from resident lymphopoietic precursors in bone marrow of postnatal mice and humans. These cells are derived from the same hemopoietic stem cells that give rise to myeloid and erythroid cells in that tissue. Although considerable information is available about regulation of immune responses and antibody production by B cells, virtually nothing is known about regulatory control of early events in B lymphopoiesis. Our laboratory has focused on defining regulatory events which potentiate the generation of pre-B cells in the marrow microenvironment. Pre-B cells are the first cells in this hemopoietic lineage to express detectable immunoglobulin heavy chain protein, the last proliferative cell stage in the lineage, and they do not self-renew. This suggests that homeostatic pre-B cell production is critical to development of the immune system. Our studies have resulted in identification of novel differentiation factors which potentiate differentiation of pre-B cells from progenitor cells. We have shown that a subset of bone marrow stromal cells produce and secrete these differentiation factors and factor secreting stromal cell lines have been established. We partially purified these differentiation factors and characterized them biologically and biochemically. Because these differentiation factors are the first to be described which regulate pre-B cell development, it is essential that we now molecularly clone and characterize them utilizing recombinant DNA technology. In this application we propose to address these goals by 1) establishing factor dependent cell lines to simplify our assay procedures for such factors, 2) generate monoclonal antibodies to these factors, 3) molecularly clone the factors secreted by a bone marrow stromal cell line, 4) isolate mRNA induced in target cells exposed to factors and generate cDNA probes for genetic analysis, 5) biochemically isolate and molecularly characterize receptors for pre-B cell differentiation factors, and 6) investigate the role of hemopoietic synergistic activities in regulation of gene expression in early B lineage cells. Our long range goals are to better understand the role of hemopoietic regulatory factors which potentiate the proliferation and differentiation of B lymphocyte precursors. This information is essential to understand failures of this hemopoietic lineage which result in immunodeficiency disease or excessive pre-B cell production which results in acute leukemias in humans.
| Billips, L G; Petitte, D; Hostutler, R et al. (1991) Suppression of bone marrow stromal cell function. Ann N Y Acad Sci 628:313-22 |
