Hematopoietic neoplasms of mice have long been used as models of human malignancies even though histologic and pathogenetic parallels have often been less than well established. In mice, high level expression of murine leukemia viruses (MuLV) from germline endogenous ecotropic viruses is associated in some strains (AKR, C58) with development of thymic T cell lymphomas in almost all mice. Remarkably, high-level virus expression from the same loci but on a different genetic background (NFS congenics, termed NFS.V+) is associated with an 80% incidence of B cell lineage lymphomas. T cell lymphomas are associated with the development of pathogenic recombinant mink cell focus- inducing (MCF) viruses while MCF viruses formed during the process of B cell transformation appear to be non-pathogenic. Histologic, phenotypic and molecular characterization of these mouse B lymphomas showed that some are strikingly similar to subsets of non-Hodgkin lymphomas (NHL) of humans but that other subsets of NHL do not appear to occur spontaneously in mice. Understandings of the molecular pathogenesis of human NHL have been advanced by the uncovering of links between cytogenetic aberrations, primarily translocations effecting activation of oncogenes - and histopathologic and immunophenotypic presentations of specific tumor types. Studies of mice have linked proviral insertional mutagenesis rather than translocations of oncogenes with lymphomas but associations of particular integration sites with specific subtypes have not been described. Studies in LIP have advanced opportunities to relate the pathogenesis of mouse and human lymphomas by defining parallels among small lymphocytic, marginal zone (MZL) and subsets of diffuse large cell lymphomas (DLCL). These lymphoma types were observed in both NFS.V+ and AKXD recombinant inbred strains but in differing proportions. One subset of DLCL was found to exhibit translocations involving BCL6, a gene implicated in the development of human DLCL. Another subset was characterized by the presence of high proportions of histiocytes providing a homologue for human histiocyte rich DLCL. Of interest, MZL occurred at very high frequency and almost exclusively in AKXD RI strains unable to express ecotropic MuLV as well as in a NZBxNZW RI-like strain, termed TAN. All lymphoma types seen in NFS.V+ mice were also seen in virus-negative segregants from a cross with NFS but with longer latencies. Ecotropic virus expression thus seems to act to accelerate the appearance of lymphomas on the NFS background. The importance and potential complexities involved in unraveling the role of MuLV in lymphomagenesis were further highlighted in a study of the spontaneous occurrence of T- and B-cell lymphoma in mice of the widely used Swiss subline, CFW, with several major findings. 1) Infection with MuLV of ecotropic and MCF classes is widespread in this colony but heterogeneous. Among randomly sampled normal mice about 50% were positive for infectious ecotropic MuLV and of these 60% also yielded MCF MuLV. 2) Ecotropic MuLV is transmitted by both genetic and epigenetic means. Evidence of the first instance is the transmission of infectious virus and one or more specific germ- line proviral integrations to progeny born of virus-positive males and virus- and sequence-negative females. Non-genetic transmission was clearly shown by the finding that virus- positive but germline sequence-negative females transmitted infectious virus to their offspring born after mating with virus- negative, sequence-negative males. 3) Tumors were found in 60% of mice; 85% were lymphomas of several morphologic types, those of B cell origin predominating. All lymphomas yielded ecotropic MuLV and most were positive for MCF MuLV. 4) Ecotropic virus isolates and mixtures of ecotropic and MCF MuLVs induced long- latency lymphoma in the low-lymphoma strain NIH Swiss when mice were inoculated as newborns. 5) Biologically, the ecotropic MuLVs of CFW mice are unusual in that, unlike isolates from other laboratory mouse strains but like Moloney MuLV, they infect the Mus dunni cell line very inefficiently. No unusual molecular structure was detected, however, in analyses of one typical Mus dunni-restricted isolate. Efforts to refine the molecular understandings of retroviral contributions to lymphoma development are centered on identifying common proviral integration sites and the genes affected by these events. These studies are detailed in AI- 00544. The observation that certain human lymphoma types, such as Burkitt lymphoma (BL), do not occur spontaneously in mice raised the possibility that species-specific differences in B cell responses to the activities of specific oncogenes might obviate their development. We examined this possibility by developing a transgene that reconstructs a BL translocation involving the MYC proto-oncogene and immunoglobulin light chain regulatory sequences. Mice bearing this transgene developed B cell lineage lymphomas with striking histologic and immunophenotypic features of human BL. In addition, these mouse BL exhibit alterations in other oncogenes like those seen in the human disease. These efforts has thus yielded the first viable small animal model for human BL.
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