The retroviruses are identified as causative agents of malignant, proliferative, and degenerative disorders in humans and other animals. Most naturally occurring retroviruses contain no genetic information to which their disease potential can be directly attributed. These viruses are thought to induce diseases, commonly malignant diseases of hematopoietic origin, through the prolonged interaction with host DNA that accompanies persistent retroviral infection. Evidence indicates that tumorigenesis by these viruses may involve proviral integration in or near particular cellular genes, the perturbation of which results in neoplastic change. Our goal is to investigate in an animal model of retroviral disease the molecular nature of these interactions. We have chosen as an animal to examine the induction of lymphoma by Feline leukemia virus (FeLV) in the domestic cat. No specific site of proviral integration is used consistently by FeLV in naturally occurring tumors. This does not preclude the possibility that a particular domain of cellular DNA is targeted consistently for proviral integration in tumor DNAs. Consistent use of particular regions of cellular DNA for proviral integration would suggest that insertional mutagenesis of those regions plays a role in malignant induction. The normal function of genes encoded in such regions is an important question, as is the mechanism by which their disruption may function in pathogenesis. It is our goal to determine (i) whether common sites of integration can be identified in feline lymphomas, (ii) the nature of the interaction between integrated provirus and gene sequences at the integration site(s), (iii) the normal function of the common integration site(s), and (iv) the mechanism by which perturbation of the site(s) is related to disease. Indeed, we have already identified a domain of feline DNA, termed Flvi-1, which harbors proviruses commonly in naturally occurring lymphomas of a particular type. Our data indicate that Flvi-1 is not related to previously identified proto-oncogenes or to common integration sites identified in other systems. Thus, Flvi-1 may represent a novel oncogene. We propose to examine the structure and expression of Flvi-1 in order to assess its function in normal and tumor tissues. Secondly, we have studied lymphomagenesis by a myc-containing strain of FeLV, termed LC-FeLV. Our studies of the appearance of thymic lymphoma following infection with LC-FeLV suggest that feline v-myc alone is insufficient to induce malignant change and that additional genetic events may be required. We propose here to examine the possibility that host DNA sequences at the sites of retroviral integration play a role in LC-FeLV lymphomagenesis.
