The purpose of this project is to characterize the function of the c-fms proto-oncogne in hematopoietic cells. Using very sensitive S1 nuclease mapping, we have identified c-fms mRNA molecules in most normal tissues including bone marrow. Expression of c-fms mRNA coincides with acquisition of other phenotypic features of the monyte-macrophage lineage on stimulation of HL-60 cells, a promyelocytic line with a phorbal ester. C-fms mRNA was also found in peripheral blood monocytes. Recently other workers have identified the c-fms gene product as the receptor for the monocyte-colony stimulating factor (M-CSF). Widespread distribution of c-fms mRNA in tissues other than those involved in hematopoiesis, demonstrated in our studies, suggest that M-CSF and its receptor may have a wider role in cell proliferation and differentiation. We had previously shown that the c-fms gene is deleted from the 5q minus chromosome, present in the bone marrow cells of patients with refractory anemia. We have now obtained evidence suggesting a decrease in c-fms mRNA in the monocytes of such patients. Given the central role of the monocyte in hematopoiesis, this gene deletion may be of pathogenic significance. To further characterize the c-fms gene product, cDNA clones have been isolated from a library constructed with normal human liver mRNA. One encodes for the entire internal tyrosine kinase domain. Fragments of this clone will be used to construct hybrid v-fms/c-fms clones with the objective of creating a functional M-CSF receptor that lacks transforming capabilities. These studies are also designed to identify modifications in the v-fms gene that result in its transforming ability.
