The central theme of this project involves the role of endogenous retroviral gene products in the genetic resistance to retrovirus induced leukemogenesis exhibited by certain strains of mice. We previously demonstrated that an endogenous retroviral env gene with two alleles is linked to the Rmcf locus on chromosome 5. One allele encodes an endogenous gp70 structurally related to that of recombinant MCF viruses, and expression of this gene in vitro results in the restriction of fibroblastic cells to infection by MCF viruses. This resistance appears to be mediated by receptor blockade (viral interference). In genetic backcross experiments this gene was shown to mediated resistance to erythroleukemia induced by neonatal inoculation with non-defective Friend murine leukemia virus (F-MuLV). Using Fluorescence Activated Cell Sorting techniques along with in vitro functional assays of hematopoietic progenitor cells we have now defined the cells in the mouse which express this gene. Expression appears to be initiated within the pool of multipotential stem cells (CFU-S) and is detectable on the majority of erythroid progenitors (BFU-E and CFU-E) as well as granulocytic precursors (GM-CFU) but is shut off at later stages of myeloid differentiation. The gene also is expressed by lymphoid progenitors which are resident in low numbers in the thymus but as in the myeloid compartment is not expressed by mature lymphocytes. This pattern of expression strongly suggests that this endogenous retroviral env gene mediates resistance to erythroleukemia by interfering with infection of primitive erythroid progenitors (presumably BFU-E) by recombinant MCF viruses generated as a consequence of infection by F-MuLV. This endogenous retroviral gene appears to define a region of chromosome 5 which is transcriptionally active during early stages of hematopoietic lineage commitment. Of interest is the close association of this gene with the Wv locus on chromosome 5 which is involved in hematopoietic stem cell function. In order to further define is structure and function we are cloning this retroviral gene from a C-DNA library.
