Dysregulated expression of hematopoietic growth factor genes may produce uncontrolled proliferation and abnormal differentiation of hematopoietic progenitors, and potentially be a factor in the production of leukemias. Retroviral vectors offer a highly efficient method for the introduction of growth factor genes, freed of normal regulatory constraints, into hematopoietic cells. Interleukin-3 is known to support the growth of early hematopoietic progenitors from multiple lineages in vitro. We had previously shown that a retroviral vector carrying the IL3 gene (N2-IL3) could infect myeloid cell lines and hematopoietic progenitors, rendering them factor-independent in vitro. When lethally irradiated or congenitally anemic mice were transplanted with N2-IL3-infected bone marrow or fetal liver cells, a striking myeloproliferative syndrome resembling human chronic myelogenous leukemia developed. The syndrome was characterized by a marked elevation of the white blood cell count, bone marrow myeloid hyperplasia with normal maturation, and massive infiltration and enlargement of the spleen and liver. Molecular analysis showed that there was proliferation of and repopulation by one or several infected stem cell clones. Bone marrow from these mice repopulated secondary recipients, and recreated in them the identical syndrome with the same stem cell clone or clones contributing. One unusual primary animal developed the syndrome by a paracrine or endocrine mechanism, with stimulation of the recipient's endogenous marrow as well as proliferation of the infected stem cell clones. Further studies are in progress to assess the contribution of autocrine versus paracrine or endocrine mechanisms in this syndrome, and to investigate whether the concurrent introduction of a transforming oncogene will produce an acute instead of a chronic leukemia.
