Leukemogenic properties of AKR dualtropic (MCF) viruses: Amplification of murine leukemia virus-related antigens on thymocytes and acceleration of leukemia development in AKR mice

Abstract

The late preleukemic period in AKR mice (6–8 months of age) is characterized by amplified expression of murine leukemia virus (MuLV)-related cell surface antigens on thymocytes. Analysis of thymic biopsies of preleukemic AKR mice at 180 days of age showed that antigen amplification was prognostic of spontaneous leukemia development within approximately 100 days. In the present study we have investigated the viral basis of this preleukemic change in AKR thymus. Cloned isolates of ecotropic, xenotropic, and dualtropic MuLV that were derived from preleukemic or leukemic AKR thymus were tested by intrathymic injection of young AKR mice to determine which of the three classes of MuLV could induce antigen amplification, and, subsequently, accelerate leukemia development in the same animal. Only dualtropic MuLV exhibited these two activities in vivo. Considerable heterogeneity was observed among the 13 dualtropic MuLV isolates examined. In vitro three distinct serological phenotypes could be recognized on the basis of expression of MuLV gag gene-coded antigens GCSA and MuLV env gene-coded antigens. G IX, G (ERLD), G (RADAI), G (ARSL2) on the surface of infected cells. Virus isolates also differed in (i) relative ecotropic-xenotropic host range (dualtropism) as assayed by ratios of infectious titers on mouse and mink cells, (ii) induction of mink cell foci (MCF), and (iii) infectivity for NIH/3T3 cells. In vivo the two activities of antigen amplification and leukemia acceleration could be dissociated and thus represent distinct virus phenotypes. Seven isolates of dualtropic MuLV induced antigen amplification; these viruses encoded G IX, G (ERLD), and G (AKSL2) antigens, were MCF inducing, had SC-1/mink titer ratios ≥ 0.4, and were infectious for NIH/3T3 cells. Only three of these virus isolates (MCF 247, MCF 69L1, and MCF 13) accelerated leukemia development. Analysis of dose-response relationships and kinetics of virus-induced antigen amplification by MCF 69L1 virus implicated virus infection of thymocytes in the preleukemic change. Moreover, the level of MuLV antigen expression on thymocytes at approximately 1 month postinjection of MCF 69L1 virus correlated directly with development of early leukemia. It is apparent that leukemia development in young AKR mice which can be induced experimentally by intrathymic injection of cloned isolates of dualtropic MuLV exhibits the hallmarks of spontaneous disease in this strain and thus can serve as a useful model for study of thymic leukemogenesis in mice.