GENETIC CONTROL OF MuLV EXPRESSION AND SPONTANEOUS LYMPHOMA IN CROSSES OF HIGH- AND LOW-LYMPHOMA STRAINS

ABSTRACT Previous studies in the crosses, AKR × BALB/c and AKR × RF, showed that alleles at the Fv-1 locus were the major factors determining the resistance of F1 mice to spontaneous lymphoma, and that these Fv-1 alleles acted by suppressing the expression of endogenous ecotropic and/or xenotropic MuLV expression. We now report studies in three new crosses, AKR × C57L, AKR × DBA/1 and C58 × DBA/2. Our findings show that Fv-1 is not a factor in the low-lymphoma phenotype of F1 mice of these crosses. Rather, one or more new genes appear to govern this resistance to lymphoma, but present evidence indicates that the mechanism of resistance in these cases also involves suppression of endogenous MuLV expression. Mice of virtually all laboratory strains develop some incidence of lymphoma, but in most strains the disease occurs only occasionally and in animals of an advanced age, i.e., more than one year old. There exist a few strains which are characterized by a high incidence of the disease, usually beginning at six to eight months of age. The best known high-lymphoma strains are AKR, C58, PL, C3H/Fg and SJL, the last of these differing from the first four in that the disease is a Hodgkin's-like reticulum cell sarcoma rather than thymic lymphoma. The discovery by Gross that cell-free extracts of lymphomatous tissues of mice of high-incidence strains could induce the disease in mice of certain low-incidence strains (1) provided the first major tool for investigation of the etiology of lymphoma. However, it was a great disadvantage that the lymphomagenic agent in these tissue extracts, called Gross virus, could be studied directly only by the extremely lengthy assay based on its capacity to induce the disease in susceptible mice. Eventually assays were developed which detected viruses derived from lymphomatous tissues AKR mice, and these retroviruses proved to be structurally similar to those identified as etiologic agents in avian leukosis. A picture has gradually emerged from intensive studies in several laboratories according to which several related but nonidentical viruses can be demonstrated in mice of high-lymphoma strains, and the genesis of the disease depends upon an interaction among these viruses. It appears that the genomes of at least two different types of retroviral genomes are integrally included in the form of DNA in the chromosomal complement of AKR mice (the most intensively studied of the high-lymphoma strains), and these endogenous genomes are transmitted by the mice as simple dominant Mendelian traits (2, 3). One type, referred to as ecotropic murine leukemia virus (MuLV), is highly infectious for cells of many mouse strains but is poorly infectious at best for cells of other animal species. Another, called xenotropic MuLV, shows a different host range, being capable of infecting certain cells of nonmurine species but not mouse cells. AKR mouse tissues show high levels of infectious ecotropic MuLV throughout life from around the time of birth (4), and xenotropic MuLV can be detected in their lymphoid tissues much later in life, from around six months of age (5). These viruses can be isolated and inoculated into mice of Gross virus-susceptible strains, but such experiments have indicated that neither virus alone has the capacity to induce lymphoma. Rather, lymphomagenicity currently appears to be a property of a third variety of retrovirus recoverable from older AKR mice (6). The genome of this type of virus does not appear to exist as such in the AKR chromosomal complement. Instead, it occurs as a result of genetic recombinations between the genomes of ecotropic and xenotropic MuLV; it shares the host range of both parental viruses, giving rise to the name, polytropic or dual-tropic MuLV. It is likely that viruses of this latter category might prove to be the active lymphomagenic principle in preparations of Gross virus.