The proliferation and differentiation of hematopoietic cells is under the control of hematopoietic growth factors. A variety of cell types are capable of producing these growth factors including endothelial cells, fibroblasts, stromal cells, monocytes and lymphocytes. Growth factors stimulate both proliferation and/or differentiation of hematopoietic cells. There is substantial redundancy in the spectra of activity of hematopoietic growth factors in that several individual factors may act on mature and immature cells of several lineages and there are several factors that have overlapping spectra of activity. Our goal is to devise strategies to determine the in vivo role of particular factors in both hematopoietic and lymphoid cell differentiation and to determine whether enhanced or reduced expression of specific growth factors can modify the proliferative advantage of neoplastic cells in vivo. Retroviral mediated gene transfer provides a highly efficient mechanism to modify the genetic dowry of primary hematopoietic stem and progenitor cells. A vector capable of transferring and expressing the gene for leukemia inhibitory factor (LIF), a factor that stimulates early hematopoietic stem and progenitor cells but that is inhibitory to leukemic cells, has been constructed for study in a murine model of acute myeloid leukemia. In another series of experiments, we have devised an expression vector that results in production of antisense RNA complimentary to the sequences of interleukin-3 (IL-3) mRNA. Transgenic mouse strains have been developed using this vector in an effort to inhibit production of IL-3 in vivo. Expression of the antisense sequences has been documented in lymphoid tissues and brain. The transgenic mice exhibit a syndrome of neurological dysfunction characterized by gait abnormalities. Several animals have developed a progressive, ultimately fatal B-cell lymphoproliferative process. These data suggest that IL-3 has a major role in neurological development and functions during lymphopoiesis to control proliferation of B cells.
