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. 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 proviral integrations in lymphomas of AKXD and NFS congenic mice that identified more than a hundred new common integration sites and a series of putative proto-oncogenes. Heightened expression of Gfi1 was foudn to be specifically associated with the development of mouse splenic marginal zone B cell lymphomas. Correlations of histologic, phenotypic and molecular characteristics of mouse leukemias and lymphomas permitteed the development of a consensus nomenclature for these malignancies. These classification systems will provide the foundation for further studies of spontaneous diseases and those modeled through the use of transgenic and knockout mice and for increased underatanding of normal B cell differentiation.Studies of diffuse large B cell lymphoma identified ICSBP as a distinguishing gene. High expression in this lymphomma subset was shown to be realted to high level expression in normal human and mouse centroblasts.ICSBP appears to regulate a series of gene critical to germinal center formation and development in humans and mice.
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