Genetic and viral factors influencing the development of spontaneous leukemia in AKR mice

Abstract

Factors influencing the development of spontaneous leukemia were studied in a genetic cross that was prepared between leukemia-prone AKR and leukemia-resistant C57BL/6 mice. Two hundred mice of the AKR x (C57BL/6 x AKR)F 1 backcross were examined for (a) the production of endogenous N-ecotropic murine leukemia virus (MuLV), (b) the production of anti-viral antibodies, (c) phenotype at the major histocompatibility complex (MHC), (d) phenotype at the Fv-1(Gpd-1) region, and (e) mortality due to leukemia or other natural causes. Although mice of this cross contained at least one genetic complement of AKR ecotropic MuL V and were expected to produce high levels of infectious virus, a variety of secondary factors influenced the level of MuLV that was detectable in extracellular fluids. The titer of ecotropic MuLV in individual mice was found to relate strongly and simultaneously to the Fv-1(Gpd-1) phenotype and to the titer of anti-viral antibodies in sera. Thus, the levels of infectious MuLV were significantly lower in mice of the Fv-1 n/b genotype and in mice that produced high titers of anti-gp70 antibodies. The production of anti-gp70 antibodies, on the other hand, was regulated independently by the MHC phenotype and the sex of the mouse. High antibody titers were found to be associated with the MHC b/k haplotype and with the female sex. Survival data derived during a 24 month period were used to determine associations between virus expression and death caused by thymic leukemia, nonthymic leukemia, and other natural causes. Regression analysis indicated that genes which mapped within the Fv-1(Gpd-1) region were the most important determinants of the risk of thymic leukemia mortality. Although there was a mild additive effect on mortality associated with the high production of ecotropic MuLV, it appeared that additional factors controlled by genes in the Fv-1(Gpd-1) region were most responsible for the dramatic susceptibility of AKR mice to thymic leukemias. Although the presence of these factors were indicated in this study, their mode of action was not defined. In addition, it was also found that the production of anti-viral antibodies influenced the mortality caused by thymic leukemias. This association, however, could be largely explained by the inverse relationship that existed between the level of detectable ecotropic MuLV and the titer of anti-gp70 antibodies. Last, it was noted that mortality caused by nonthymic leukemias was not significantly influenced by phenotypic variation in either the Fv-1(Gpd-1) region or in the expression of ecotropic MuLV. This finding suggested that leukemias of thymic and nonthymic origin had different etiologies.