AUTOCRINE GROWTH-FACTOR SECRETION AFTER TRANSFORMATION OF HUMAN CYTOKINE-DEPENDENT CELLS BY VIRAL AND CELLULAR ONCOGENES

The effects of viral and cellular oncogenes on a human erythroleukemic cell line (TF-1) were investigated. The TF-1 cell line required granulocyte/macrophage-colony stimulating factor (GM-CSF) for growth but this factor-dependency was abrogated by the constitutive expression of either viral (v-fms, v-Ha-ras and v-src) or cellular oncogenes (BCR-ABL and Delta N-raf). Furthermore the overexpression of the human insulin-like growth factor-1 (IGF-1) receptor could substitute the dependency on GM-CSF with a requirement for either IGF-1 or insulin as a proliferative signal. An autocrine cytokine, (GM-CSF) was found in the supernatant of cells transformed by Delta N-raf (and to a lesser extent in cells infected with other oncogenes. The level of GM-CSF secreted by the Delta N-raf transformants was sufficient to support the proliferation of the parental cell line. GM-CSF mRNA transcripts were detected in the Delta N-raf-infected but not in the parental cells. No structural alterations of the GMCSF locus were seen in these cells. Together these observations indicated that overexpression of a raf oncogene resulted in the expression of GM-CSF transcripts. The rates of glucose transport were elevated above basal levels by GMCSF and by oncogene expression indicating that this pivotal control point of metabolism correlated with mitogenesis and malignant transformation. These studies indicate the importance of raf in growth regulation as its deregulation can lead to autocrine synthesis of cytokines in certain hematopoietic cells. Furthermore these results suggest a synergy between oncogene and cytokine gene regulation leading to autocrine growth factor expression and tumor progression.