ONCOGENIC EFFECTS OF OVEREXPRESSION OF THE INTERLEUKIN-3 RECEPTOR ON HEMATOPOIETIC-CELLS

To elucidate the relationship between malignant transformation and cyt okine receptor expression, the interleukin-3 receptor (IL-3R) complex was examined in an IL-3-dependent parental line and cells transformed by cytokines and oncogenes. In IL-3-dependent cells grown in medium co ntaining optimum amounts of IL-3, the IL-3R complex was detected at lo w levels indicating that the receptor was down-regulated in response t o IL-3. However, upon depletion of IL-3, IL-3R levels increased docume nting that its expression correlated inversely with the concentration of IL-3 provided. In contrast, more IL-3 receptors were observed const itutively in autocrine-transformed derivative lines, which secreted su boptimal amounts of IL-3. To examine the effects of activated oncogene s on IL-3R expression in autocrine-transformed cells, the cells were i nfected with retroviral vectors containing various oncogenes. Decrease d levels of IL-3R expression were observed in the oncogene-infected ce lls. These studies imply that important regulatory cross-talk occurs b etween ligands and their cognate receptors in cytokine-dependent hemat opoietic cells. Deregulation of this ligand-receptor interaction in th e oncogene-infected cells may be a consequence of the cells using modi fied signal transduction pathways which bypass the IL-3:IL-3R interact ion. To determine the effects of IL-3 receptor overexpression on the c ytokine dependency of hematopoietic cells, IL-3R alpha and beta cDNAs were inserted into retroviral vectors. Overexpression of either the al pha or beta chains did not directly relieve factor dependency, however , constitutive expression of the IL-3R alpha allowed the cells to prol iferate in suboptimal concentrations of IL-3. Moreover, factor-indepen dent transformants were subsequently isolated from pools of cells infe cted with viruses containing either the alpha or beta receptor cDNAs a t a frequency of approximately 1 in 10(3) to 10(4) cells whereas such cells were not recovered from control cells. Deregulation of IL-3 rece ptor chain gene expression may provide a proliferative advantage to he matopoietic cells growing under conditions in which the cytokine is li miting and allow the development of a leukemia.