Accelerated Appearance of Multiple B Cell Lymphoma Types in NFS/N Mice Congenic for Ecotropic Murine Leukemia Viruses

Abstract

SUMMARY:Spontaneous lymphomas occur at high frequency in NFS.V ϩ mice, strains congenic for ecotropic murine leukemia virus (MuLV) proviral genes and expressing virus at high titer. In the present study, a total of 703 NFS.V ϩ lymphomas were studied by histopathology, immunophenotypic analysis, immunoglobulin heavy chain or T cell receptor ␤ chain rearrangements, and somatic ecotropic MuLV integrations; 90% of the lymphomas tested were of B cell lineage. Low-grade tumors included small lymphocytic, follicular, and splenic marginal zone lymphomas, while high-grade tumors comprised diffuse large-cell (centroblastic and immunoblastic types), splenic marginal zone, and lymphoblastic lymphomas. Comparison of mice of similar genetic background except for presence (NFS.V ϩ ) or absence (NFS.V Ϫ ) of functional ecotropic MuLV genomes showed that NFS.V Ϫ clonal lymphomas developed at about one-half the rate of those occurring in NFS.V ϩ mice, and most were low-grade B cell lymphomas with extended latent periods. In NFS.V ϩ mice, clonal outgrowth, defined by Ig gene rearrangements, was associated with acquisition of somatic ecotropic proviral integrations, suggesting that, although generation of B cell clones can be virus independent, ecotropic virus may act to increase the rate of generation of clones and speed their evolution to lymphoma. The mechanism remains undefined, because only rare rearrangements were detected in several cellular loci previously associated with MuLV insertional mutagenesis. (Lab Invest 2000, 80:159-169).O ne of the earliest mammalian animal models in cancer research was the AKR mouse strain developed by Jacob Furth about 70 years ago. Selective breeding yielded mice with nearly 100% mortality due to thymic lymphoma in 7 to 14 months (Cole and Furth, 1941). AKR and the limited number of other T cell lymphoma-prone mouse strains (C58, HRS, and some AKXD recombinant inbred (RI) lines) (Gilbert et al, 1993;Green et al, 1980;MacDowell and Richter, 1935;Meier et al, 1969;Mucenski et al, 1986Mucenski et al, , 1988 have been intensively studied, yielding a partial molecular understanding of the role of ecotropic and recombinant mink cell focus-inducing (MCF) murine leukemia viruses (MuLV) in pathogenesis of this earlyonset lymphoma (Cloyd et al, 1980;Hartley et al, 1977;Holland et al, 1985; M c Grath and Weissman, 1979;Rowe and Hartley, 1983;Stoye et al, 1991;Thomas et al, 1984). In contrast to those of T cell lineage, spontaneous B cell lymphomas are most commonly seen in aged mice of strains in which T cell lymphoma does not predominate. For example, the incidence of B cell lymphoma of various types may be 30% or more in unmanipulated, aged BALB/c, C57BL (Frith and Wiley, 1981), AKR.Fv-1 b (HaranGhera et al, 1993), CWD (Angel and Bedigian, 1984;Mucenski et al, 1988;Thomas et al, 1989), or certain AKXD RI lines (Gilbert et al, 1993;Mucenski et al, 1986) held for up to 3 years, as well as in thymectomized AKR (Peled and Haran-Ghera, 1985) and Emyc transgenic mice (Adams et al, 1985). In SL/Kh (Shimada e...

Anaplastic, Plasmablastic, and Plasmacytic Plasmacytomas of Mice: Relationships to Human Plasma Cell Neoplasms and Late-Stage Differentiation of Normal B Cells

“…Histologic diagnoses were made according to the Bethesda classification of mouse lymphoid neoplasms (2). Features of diffuse large B-cell centroblastic and immunoblastic lymphomas have been described (2,24). Immunohistochemical studies were done using the panel of antibodies listed in Supplementary Table S1 and procedures described previously (26).…”

“…Published studies from our laboratories and others have revealed that these plasmacytomas are heterogeneous and can be divided into subtypes based on histologic features and gene expression profiles, some with human counterparts (18)(19)(20)(21)(22)(23). Here, we describe a new set of mouse plasmacytomas that developed in NFS.V + mice (24). Histologically, they comprise three subsets-low grade/plasmacytic, intermediate grade/plasmablastic, and high grade/anaplastic-that closely parallel the terminologies suggested by Bartl et al (9) for variants of human multiple myeloma.…”

High-Throughput Retroviral Tagging for Identification of Genes Involved in Initiation and Progression of Mouse Splenic Marginal Zone Lymphomas

“…NFS.V ϩ mice congenic for ecotropic MuLV induction loci from strains AKR and C58 and that develop a high incidence of B-cell lymphomas of different histological types have been described previously (11). Samples obtained at autopsy were frozen for later preparation of DNA and RNA and for histopathology.…”

IL-6 transgenic mouse model for extraosseous plasmacytoma

“…Tissues were classified as exhibiting plasma cell abnormalities including: (i) plasmacytosis, accumulations of normal-appearing, and nondividing plasma cells; (ii) plasma cell hyperplasia (PCH), mixtures of normal and aberrant hyperchromatic, sometimes mitotically active plasma cells; (iii) microplasmacytoma (mPCT), isolated clusters of malignant plasma cells, presumptive precursors of overt PCT; (iv) PCT; and (v) anaplastic plasmacytoma (PCT-A), a mixture of immunoblasts and plasma cells with Ͼ90% of cells being immature forms of malignant plasma cells. Nonplasmacytic lymphoid neoplasms were classified as follicular B cell lymphoma (FBL) or diffuse large-cell B cell lymphoma (DLCL), using criteria described in a provisional system of nomenclature for mouse hematopoietic tumors (13,14). Avidin-biotin immunoperoxidase techniques with antisera to IgL and IgH (Southern Biotechnology Associates), B220 (CD45R) (CalTag), and CD19 and CD138 (syndecan; PharMingen) were used for the determination of Ig production and surface marker expression as described (11).…”