OVEREXPRESSION OF PDGF-B IN MURINE HEMATOPOIETIC-CELLS INDUCES A LETHAL MYELOPROLIFERATIVE SYNDROME IN-VIVO

Although PDGF is not a primary hematopoietic cytokine, effects in hema topoietic cell cultures have been reported. We recently described resp onses of multilineage hematopoietic precursors to PDGF. The effects we re shown to be neutralized by antibody to LL-1 beta and mediated by ma rrow macrophages that expressed PDGF receptor RNA and responded to PDG F by upregulation of IL-1 RNA. The present study was performed to dete rmine whether constitutive expression of PDGF by hematopoietic cells w ould have hematopoetic consequences in vivo. Retroviral vectors contai ning a PDGF-B gene were constructed and infected into normal marrow ce lls. Irradiated mice reconstituted with infected cells consistently de veloped a lethal myeloproliferative syndrome with anemia, neutrophilia and monocytosis, declining hematopoiesis in marrow with shift to the spleen, and extensive infiltration of immature hematopoietic cells int o the parenchymal organs and connective tissues. In addition to PDGF, the retroviral constructs expressed a nea resistance marker. Phenotypi c expression patterns in fibroblasts and in hematopoietic colony-formi ng cells in vitro were consistent with a significant degree of interac tion between the two expressed inserts. Moreover, selection of infecte d cells for G418 resistance significantly reduced not only the number of infected reconstituting cells but also the intensity of the evoked syndrome in vivo. The observations have important implications for pro jected gene therapy protocols, and identify a novel potential pathway to myeloproliferative disease.