Studies in our laboratory have demonstrated that macrophages can directly affect erythropoiesis, both in vitro and in vivo. The pattern of this effect parallels precisely the ability of macrophages to reverse leukemia. Using a unique model system developed in our laboratory, we have found that macrophage regulation of erythropoiesis is impaired in leukemia. Regulation is restored and the leukemia reversed by the transfer of normal macrophages. When macrophages are transferred to normal or leukemic animals, erythroid colony formation (CFU-E) is significantly suppressed. The data suggest that macrophages do not suppress erythropoiesis in vivo through regulation of EPO levels but by an influence on an erythropoietic stimulatory factor. This factor is present only in impure preparations of EPO and can only be measured by the in vitro fetal liver assay and not by the traditional in vivo standard plasma EPO assay. No suppressive activity has been detected by normal macrophages in vitro. The production in vitro of a CFU-E stimulatory factor by virus-infected macrophages correlates with the failure of leukemic animals to experience regression. Our goals for the coming year are: (1)\to extend our present studies to include isolation and characterization of the factor related to EPO that appears to be regulated either directly or indirectly by normal macrophages; (2)\to determine the factor's role in vivo in regulation of erythropoiesis; and (3)\to characterize the in vitro stimulatory factor produced by virus-infected macrophages. (MB)