Using three different systems, studies have been aimed at understanding the mechanisms by which retroviruses cause erythroleukemia in mice and identifying the viral and host genes that are crucial for the biological effects observed. Studies on the acute erythroleukemia-inducing Friend spleen focus-forming virus have concentrated on understanding how the viral envelope protein abrogates the erythropoietin (Epo) requirement of erythroid cells. The protein appears to interact with and trigger the Epo receptor, and studies are in progress to determine if this interaction results in a mitogenic signal like that initiated by Epo. We have also been studying the effects of another erythroleukemia-inducing virus, the gag-myb-ets-containing ME26 virus, on hematopoietic cell growth. Our results indicate that this virus, which encodes a DNA-binding protein, may be activating the Epo receptor in an immature hematopoietic cell that does not normally express it. The virus, however, may not be directly transactivating the Epo receptor, but may be working through another erythroid-specific gene, GATA-1. Studies on the third erythroleukemia-inducing virus, Friend MuLV, have been twofold. We have molecularly cloned a candidate for a host gene, Rmcf-r, that is involved in resistance to early erythroleukemia induced by the virus, and are now testing its biological activity. We have also molecularly cloned a variant of Friend MuLV, PVC-211, which no longer causes erythroleukemia in mice, but which induces a progressive neurodegenerative disease. We are now generating recombinants between PVC-211 and wild-type Friend MuLV in order to localize the regions of the viral genome responsible for inducing either leukemia or neurological disease.
