Phenotypic heterogeneity of spontaneous lymphomas of CWD mice

Recombinant murine leukemia viruses (MuLVs) from high-leukemia-incidence mouse strains typically acquire pathogenic U3 region sequences from the genome of the endogenous xenotropic virus, Bxv-1. However, a recombinant virus isolated from a leukemic HRS/J mouse and another from a CWD mouse contained U3 regions that lacked genetic markers of Bxv-1. The U3 regions of both recombinants were derived from the endogenous ecotropic virus Emv-1 and had retained a single enhancer element. However, compared with that ofEmv-1, the U3 region of each of the recombinant viruses contained five nucleotide substitutions, one of which was shared. To determine the biological significance of these substitutions, chimeric ecotropic viruses that contained the U3 region from one of the two recombinant viruses or from Emv-1 were injected into NIH Swiss mice. All three of the chimeric ecotropic viruses were leukemogenic following a long latency. Despite the presence of an enhancer core motif that is known to contribute to the leukemogenicity of the AKR MuLV SL3-3, the HRS/J virus U3 region induced lymphomas only slightly more rapidly than the allelic Emv-1 sequences. The chimeric virus with the U3 region of the CWD recombinant caused lymphomas more frequently and more rapidly than either of the other two viruses. The results support the hypothesis that one or more of the five nucleotide substitutions in the U3 regions of the recombinants contribute to viral pathogenicity. Comparison of DNA sequences suggests that the pathogenicity of the CWD virus U3 region was related to a sequence motif that is shared with Bxv-1 and is recognized by the basic helix-loop-helix class of transcription factors.

Section: Construction Of Chimeric Proviruses Standard Recombinantsupporting

confidence: 74%

Pathogenic determinants in the U3 region of recombinant murine leukemia viruses isolated from CWD and HRS/J mice

Lawrenz-Smith

Massey

Innes

et al. 1994

“…Extraction of genomic DNA and Southern blotting of the tumor DNAs were performed as described previously (35). The immunophenotype of the tumors was based on histopathologic testing, the presence or absence of immunoglobulin and T-cell receptor gene rearrangements, and immunocytochemical analysis by techniques detailed in an earlier report (49). The probes for gene rearrangement studies included portions of the J regions of the immunoglobulin heavy chain (JH) and kappa light chain (JK) and the constant region of the murine T-cell receptor beta chain.…”

Section: Methodsmentioning

confidence: 99%

Origins of enhancer sequences of recombinant murine leukemia viruses from spontaneous B- and T-cell lymphomas of CWD mice

Massey

Lawrenz-Smith

Innes

et al. 1994

Recombinant murine leukemia viruses from the highly leukemic mouse strains AKR, HRS, and C58 usually acquire pathogenic U3 region sequences from the endogenous xenotropic virus, Bxv-1. However, the majority of tumors from another highly leukemic strain, CWD, contained recombinant viruses that lacked Bxv-1-specific sequences. The nucleotide sequence of the U3 regions of two such CWD recombinants was nearly identical to that of the endogenous ecotropic virus parent Emv-1, but they shared three nucleotide substitutions immediately 3' of the enhancer core. These substitutions were found in recombinant proviruses from about one-third of spontaneous CWD lymphomas as determined by an oligonucleotide hybridization assay of proviral fragments that had been amplified by PCR. Analysis of amplified endogenous murine leukemia virus sequences suggested that the three nucleotide substitutions in the CWD viruses were inherited from an endogenous polytropic provirus that is absent in the other highly leukemic strains. On the basis of the results of these and previous studies, we propose that CWD recombinants acquire pathogenic U3 region sequences through recombination with an endogenous polytropic virus or Bxv-1 and that the pathogenicity of these sequences may be related to a sequence motif that is known to bind members of the basic helix-loop-helix class of transcription factors.

“…Ten HRS/J and 14 CWD mice were monitored until death or were sacrificed because of advanced disease. The presence of lymphoma was confirmed by necropsy and histologic examination of tumor tissues (33).…”

Section: Methodsmentioning

confidence: 99%

An increase in disease latency is associated with a host-dependent selection for recombinant murine leukemia viruses with substitutions in the p15E (TM) gene

Thomas

Coppola

Nuckols

et al. 1993

The genomes of recombinant murine leukemia viruses recovered from HRS/J (type I env recombinants) and CWD (type II env recombinants) mice have distinct envelope gene structures. To better understand the biologic significance of these differences, we examined the differences in the responses of HRS/J and CVD mice to inoculation with an oncogenic type II env recombinant. The CVD recombinant accelerated the onset of lymphoma in both strains, but the disease latency in the HRS/J mice was about 2 months longer. Analysis of the recombinant viruses in the HRS/J tumors revealed that the injected type II env recombinant had recombined in vivo with the endogenous ecotropic viruses to generate secondary recombinants with type I envelope genes. In another set of experiments, comparison of complete or partial DNA sequences of the envelope genes from six recombinant proviruses confirmed that the origins of the sequences that encode an amino-terminal region of the TM envelope protein, plSE, distinguish type I envelope genes from type II. Taken together with the results of previous studies, these observations suggest that the differences in the responses of HRS/J and CWD mice to the oncogenic type II env recombinant resulted from an interaction between the viral TM protein and a host factor expressed in HRS/J mice.