The proliferation and differentiation of hematopoietic cells in under both the positive and negative control of hematopoietic growth factors. Our goal has been to devise strategies to determine the in vivo role of particular factors in both hematopoietic and lymphoid cell differentiation, as well as the effect of hematopoietic growth factors in normal versus malignant hematopoiesis. 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, and IL-3 production by splenocytes in these mice is decreased. The mice exhibit a neurological syndrome characterized by cerebellar degeneration, suggesting that IL-3 or an IL-3 related protein may have a role in neurological function. The mice also develop a rapidly fatal lymphoma composed of primitive B cells suggesting that IL-3 may have a critical, physiological role in controlling the growth of early, undifferentiated B-cells. We are now using a similar strategy to study the in vivo role of gp130, the common transducing component of a family of cytokine receptors, including IL6, Il11, LIF, oncostatin M, and CNTF. A second series of projects focuses on the role of transforming growth factor beta in hematopoiesis. We have shown that it is potently inhibitory to murine hematopoietic progenitors and primitive CFU-S, as well as true repopulating stem cells. Inhibition of autocrine or paracrine production of TGF-beta is stimulatory to progenitor and stem cells. This information may allow better ex vivo stem cell expansion and susceptibility to gene transfer. We have also been studying the differential effect of stem cell factor on malignant versus residual benign marrow progenitor cells from patients with CML. In long-term culture the use of SCF-deficient stroma gives benign cells an advantage. This finding may eventually lead to improved purging in CML autologous transplantation.
