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    Characterization of LP-BM5 defective retrovirus induced T-cell lymphomagenesis in murine acquired immunodeficiency disease

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    Author
    Campbell-Washington, Judith
    Advisor
    Eiseman, Julie L.
    Date
    1995
    Type
    dissertation
    
    Metadata
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    Abstract
    LP-BM5, a non-acute transforming murine leukemia virus (MuLV) mixture containing the disease inducing, oncogenic defective virus (BM5d), and ecotropic (BM5eco) and mink cell focus-forming (MCF) helper viruses was used to induce murine acquired immunodeficiency syndrome (MAIDS) and lymphoid neoplastic transformations in adult C57BL/6 mice. During early-stage ({dollar}\leq{dollar}8 wks p.i.) MAIDS disease, non-neoplastic or hyperplastic polyclonal proliferation of both T- and B-cells occurs. Progression of MAIDS disease led to clonal expansion of fully malignant lymphomas which developed only during late-stage ({dollar}\geq{dollar}16 wks p.i.) In contrast to previous studies, predominately T-cell lymphomas, rather than B-cell lymphomas, arose at high frequency (89%) in primary late-stage MAIDS mice. Studies were designed to characterize the disease sequelae and frequency of lymphomagenesis in late-stage MAIDS. Spleen or lymph node cells from adult C57BL/6 mice, which had received 0.1 mg/ml 3{dollar}\sp\prime{dollar}-azidothymidine (AZT) administered ad libitum in drinking water, and had survived past late-stage MAIDS, were transplanted by intraperitoneal (i.p.) injection into C.B-17 severe combined immunodeficient (SCID) mice followed by sequential passage into C57BL/6 syngeneic recipient mice. Analysis of the immunophenotypic profiles and the malignant potential of primary and passaged lymphomas, demonstrated that predominately CD4+ T-cell lymphomas which were aggressively malignant were developed. Although 61% (8/13) of the primary lymphomas from late-stage MAIDS mice were tumorigenic in SCID recipients, only half (4/8) of the lymphomas which were tumorigenic in SCID recipients exhibited frank malignancy in syngeneic recipient mice. Genotypic analysis of T-cell receptor {dollar}\beta{dollar}-chain (TCR{dollar}\beta{dollar}) and immunoglobulin heavy chain (IgH) gene rearrangements confirmed that all but one of these lymphomas originated from clonal expansion of fully transformed mature T-cells which showed clonal rearrangements of TCR{dollar}\beta{dollar} chain genes. Based upon concordance of the TCR{dollar}\beta{dollar} and IgH gene rearrangement patterns of each individual tumor, throughout sequential passages, these lymphomas consistently disseminated into and predominated the lymphoid tissues upon transplantation in SCID recipients, and particularly in the case of the T-cell lymphomas, in immunocompetent syngeneic recipients. Molecular analyses using polymerase chain reaction (PCR) DNA amplification and Southern blot hybridizations have demonstrated that all of these clonal lymphomas contained integration(s) of BM5d proviral DNA. Molecular analyses were also conducted to determine insertional mutagenesis or alterations of specific cellular oncogenes, such as c-myc and pim-1. Although no rearrangements of pim-1 were detected in any of these lymphomas, c-myc was rearranged in 2 of 5 of these T-cell lymphomas. It is still unclear however, if the c-myc alterations observed in these two lymphomas were caused by insertion of the BM5d provirus or either of the BM5eco or MCF7 helper proviruses which constitute the LP-BM5 virus pool. In summary, we have characterized the disease sequelae and frequency of lymphomagenesis in late-stage MAIDS. Clonal lymphomas developed in 61% of SCID mice inoculated with lymphocytes from primary late-stage MAIDS mice, the majority of which were CD4+ T-cell lymphomas. Although all tumors contained integration(s) of BM5d provirus, only 2/5 lymphomas had detectable alterations of c-myc which appear to be associated with insertion of at least one of the LP-BM5 proviruses.
    Description
    University of Maryland, Baltimore. Ph.D. 1995
    Keyword
    Biology, Molecular
    Biology, Genetics
    Biology, Microbiology
    T-cell lymphomagenesis
    Murine Acquired Immunodeficiency Syndrome
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/1533
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    Theses and Dissertations All Schools

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