Association of recombinant murine leukemia viruses of the class II genotype with spontaneous lymphomas in CWD mice

Abstract

We determined the phenotype and genotype of murine leukemia viruses associated with the development of spontaneous nonthymic lymphomas in the high-leukemia mouse strain CWD/J. By T, oligonucleotide fingerprint analysis of the viral RNA, the ecotropic viruses recovered from the spleen or thymus of preleukemic CWD/J mice were found to represent the progeny of the two endogenous ecotropic proviruses present in this strain. Polytropic murine leukemia viruses were produced by tissues from one-half of the leukemic mice, and fresh tumor cells from one of the two animals tested expressed recombinant envelope glycoproteins. The genomic structure of the recombinant viruses resembled those of class II polytropic viruses of NFS * Akv mice and differed from those of class I recombinant viruses that are commonly isolated from other high-leukemia strains such as AKR and HRS. Acquired retroviral sequences with the structural features of class II recombinant proviruses were detected in the DNA from each CWD/J tumor by the Southern blot technique. Finally, the injection of a mixture of CWD/J ecotropic and class II recombinant polytropic viruses into neonatal CWD/J mice accelerated the onset of lymphoma, whereas the endogenous ecotropic virus was inactive in these assays.

Comparative molecular genetic analysis of lymphomas from six inbred mouse strains

“…CWD/LeAgl mice, like HRS/J mice, express high titers of ecotropic virus early in life, yet they are highly susceptible to B-cell lymphomas containing ecotropic but not class I MCF proviruses. Recently, Thomas et al (52) identified class II MCF viruses in lymphomas of CWD/ LeAgl mice. These viruses were shown to accelerate the onset of lymphomas when injected into neonatal CWD/ LeAgl mice.…”

The MouseH-2ARegion Influences the Envelope Gene Structure of Tumor-Associated Murine Leukemia Viruses

“…We had previously shown that the presence of type I or type II recombinants within lymphoma cells is influenced by a host gene located on mouse chromosome 17. In these experiments, the injection of the ecotropic SL3-3 MuLV induced tumors and type I recombinants in HRS/J mice, whereas tumors from injected CWD mice contained type II recombinants (6,32,37). The type I-forming phenotype (TI) of HRS/J mice was dominant with respect to the type II-forming phenotype (TII) of CWD mice and segregated with restriction fragment length polymorphisms on chromosome 17 which are located within the H-2 locus, the mouse major histocompatibility complex.…”

“…This allows for the selection of those variants that replicate more efficiently and are more pathogenic than the original dominant species in the viral population. In the inbred mouse strains AKR, HRS, C58, and CWD, the generation and selection of pathogenic recombinant murine leukemia viruses (MuLVs) is an important step in the development of spontaneous lymphomas (3,5,13,15,17,23,32,33,35). Animals of these strains express early in life endogenous ecotropic MuLVs that subsequently acquire pathogenic sequences by recombination with endogenous polytropic and xenotropic viruses.…”

“…The recombinants typically incorporate 5Ј envelope gene sequences from one or more of the 20 or so endogenous polytropic viruses. This portion of the gene encodes the receptor binding domain of the major envelope protein, SU or gp70, and thus confers a polytropic host range (2,3,5,13,15,17,23,27,32,33,35). The polytropic domain within gp70 appears to promote leukemogenesis by enhancing virus replication in lymphoid target cells and through the activation of growth factor signaling pathways (3,22,39).…”

“…The MuLV envelope gene (env) encodes a common precursor protein, gp85, that is cleaved to yield two products, the mature gp70 and the minor envelope protein, TM or p15E (12,43). The 5Ј portion of the gp70 gene of the recombinant viruses is composed of sequences inherited from the endogenous polytropic viruses, but the 5Ј portion of the p15E gene may be de-rived from either the ecotropic or polytropic virus parent (6,23,32,35,37). Recombinants in which the 5Ј p15E gene contains ecotropic virus sequences are classified as type I recombinants, whereas those that acquire the allelic polytropic virus sequences in this region are designated type II recombinants ( Fig.…”