Malignant transformation of normal cells occurs as a consequence of dysregulated expression of proto-oncogenes or mutations in such genes that result in the synthesis of an abnormal product. Retroviral mediated gene transfer provides a highly efficient mechanism to modify the genetic dowry of primary hematopoietic stem and progenitor cells. Genes for hematopoietic growth factors, their receptors or mutated forms of normal cellular genes can be introduced, singly or in combination. The hematopoietic syndromes or neoplasms that result bear witness to the transforming capacity of the introduced genes and provide models for specific therapeutic intervention targeted to a dysregulated genes or an abnormal gene product. Moreover, dysregulated expression of a growth factor gene provides a unique opportunity to characterize its spectrum of biological activity. Previously, we have characterized the myeloproliferative syndrome induced by IL-3 and a lymphoproliferative process resembling the human disease - Castleman's Syndrome - produced by IL-6. Using a competitive repopulation assay, we have investigated the effects of autocrine stimulation by IL-3 or IL-6 on stem cell self-renewal. We have found that the stem cell pool in animals exhibiting the IL-3 or IL-6 syndrome remains heterogenous and is composed of predominantly non-retroviral containing cells. Leukemia inhibitory factor (LIF) stimulates early normal hematopoietic stem and progenitor cells but is inhibitory of leukemia cell growth. A vector capable of transferring and expressing the LIF gene has been constructed for study in a murine model. Ultimately, it may prove useful in enhancing normal versus leukemic cell growth in human marrow.
