The long-term goal of this program is to identify the multiple events that interplay in the pathogenesis of lymphoid malignancies in the domestic cat. This outbred species has the highest incidence of leukemia-lymphoma of any animal, and horizontal infection by the naturally occurring feline leukemia virus is related to its increased susceptibility to leukemogenesis. Events that occur during the prolonged viremic period are mostly unknown, except that infected cats become immunosuppressed and that in many thymic lymphomas the c-myc proto-oncogene is either transduced or insertionally activated. While the proximal leukomogens for the disease are unknown, there is evidence for homologous recombination between viral and endogenous cellular retrovirus elements. The characterization of these endogenous sequences of the domestic cat genome and isolation of two commonly occurring alleles of the feline c-myc gene provide the basis for the present study. There is evidence that one type of homozygosity at the c- myc locus is rare, while the other type of homozygosity that commonly occurs in cats may be associated with increased frequency of lymphomas.
The specific aims are as follows: (1) examine the role of specific viral subgroups and recombination between endogenous and exogenous retroviral genes in dictating in vivo tissue tropism and disease specificities; (2) examine the impairment of the host's immune response by the variants to identify the viral determinants for immunosuppression; (3) determine genetic properties of the isolated c-myc alleles in terms of functional and structural differences and confirm that the observations extend generally to the detection of similar structural changes in cat genomic DNAs; and (4) identify the proximal agents that are involved in the rearrangement of the c-myc gene and determine if there is allele specificity for activation and consequent biological activity. The model system offers the opportunity of examining the interaction between exogenous and endogenous retrovirus genes and between provirus elements and a widely implicated proto-oncogene with biologically significant allelic variations in the development of lymphoid tumors in an outbred animal species.
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