Autocrine Proliferation and Differentiation-Capacities of Leukemic Cells, and Molecular Analyses of Leukemic Phenotypes

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Normal hemopoietic progenitors proliferate and differentiate to produce mature functioning cells, depending on a variety of hemopoietic growth factors, of which genes have been recently cloned. In contrast, autocrine growth mechanism(s) have been proposed especially at the onset of leukemia, a type of hemopoietic malignancy, since leukemia have been considered to develop from the transformation and clonal proliferation of hemopoietic precursors. The concept of autocrine mechanism(s) of cellular proliferation suggests that a cell can both produce and respond to a particular growth factor. Then, under certain conditions, such a cell might become independent of external growth regulation in a manner that would lead to malignant transformation. In order to elucidate the mechanism of malignant transformation of hemopoietic cells, we investigated the tumorigenicity of FDC-P2, an IL-3-dependent murine myeloblastic cell line established from a long-term culture of normal bone marrow cells, aft … More er transfection of the cDNA encoding murine IL-3 by electroporation. Two sublines growing in the absence of growth factors were established. Southern blot analysis using the probe of IL-3 gene showed that one cell line contained one copy of the integrated IL-3 gene, and the other contained 2-3 copies. A significant amount of IL-3 was detected in cutured media of these cell lines. These results suggest that the expression of IL-3 gene and the secretion of IL-3 transformed IL-3-dependent cells to IL-3-independent cells. Subcutaneous transfer of these cells into nude mice consistently produced tumors. The capacity of the transfected cells producing IL-3 appeared to confer a tumorigenic phenotype to these cells. Similar results were obtained with another murine myelomonocytic cell line, NFS-60 cells. In the latter case, 10 clones which became independent of IL-3 were established after transfection with IL-3 gene into the parental IL-3-dependent cell line. The capacities to produce IL-3 outside the cell were varied with different clones. However, the IL-3 activity inside the cell was found not to be much less different among the clones. Thus, the intracellular IL-3 activity was considered to be crucial for the autocrine growth of the transformed cells produced by transfection of the growth factor gene. Less