EVIDENCE THAT RAS AND MYC MEDIATE THE SYNERGY BETWEEN SCF OR M-CSF AND OTHER HEMATOPOIETIC GROWTH-FACTORS

We previously reported that M-CSF could mimic the synergistic effect o f SCF upon myeloid FDC-P1 cells that were first infected with a c-fms retrovirus, which encodes the human M-CSFr. We now report that an M-CS Fr with a mutation of its autophosphorylation site at position 809 was , in response to M-CSF, unable both to synergize with IL-3 or GM-CSF a nd to induce c-myc; whereas a mutant receptor with a deletion of its k inase insert was unaffected for these processes. The expression of an exogenous c-myc proto-oncogene or a H-12-ras oncogene lowered the requ irement of FDC-P1 cells for IL-3 or GM-CSF, in a similar manner to M-C SF or SCF addition. Furthermore, the expression of either of these gen es complemented the defective M-CSFr F809. These results strongly supp ort a role for ras and myc in the synergistic action of M-CSF and, by implication, of SCF, which implies that these signalling intermediates are rate-limiting for the action of IL-3 and GM-CSF and possibly othe r haemopoietic growth factors.