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. An activated form of the RAS oncogene causes thymic lymphomas in mice. Retroviral vectors containing the IL-4, IL-7, IL-9 and the M-CSF coding sequences have been constructed and used for gene transfer into hematopoietic stem cells. IL-4 and IL-7 act predominantly on lymphoid progenitors, M-CSF is specific late stage monocytes and macrophages and IL-9 is a newly discovered growth factor that seems to act predominantly on primitive erythroid progenitors. Current efforts are focused on characterizing the effects of overexpression of these genes during regeneration of the hematopoietic and lymphoid systems in transplanted mice.
