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    • Albert Einstein College of Medicine: Doctoral Dissertations
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    • Albert Einstein College of Medicine (AECOM)
    • Albert Einstein College of Medicine: Doctoral Dissertations
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    Transcriptional, pathological and genetic analysis of retroviral tumorigenesis

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    Date
    2000
    Author
    Trubetskoy, Alla M.
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    Abstract
    My thesis examined two aspects of retroviral molecular genetics. First, a study of a novel element within the viral genome that appears to control the transport of viral RNA. Sequences at the very 5'-end of MuLV transcripts form a stem-loop structure and are important for the maximum levels of expression of retroviral genomes. These R-region sequences and stem-loop structure were shown to be important for the expression of a gene from an unspliced transcript, but not from an efficiently spliced transcript.;Second, Moloney murine leukemia virus (Mo-MuLV) was used to infect INK4a homozygous knockout, heterozygous and wild type mice. The INK4a locus encodes two tumor suppressors, p16INK4a and p19ARF, and is frequently inactivated in tumors. Others showed that, INK4a deficient mice spontaneously developed sarcomas, B-cell lymphomas, and extramedullary hematopoiesis (EMH).;Infection of INK4a deficient mice with Mo-MuLV accelerated the onset of disease as compared to uninfected, INK4a deficient mice and to the infected, wild type and heterozygous mice. Mo-MuLV infected, INK4a heterozygous and wild type mice mostly developed T-cell lymphomas. Mo-MuLV infected, INK4a deficient mice developed T-cell lymphomas, B-cell lymphomas, sarcomas, and EMH of increased severity and faster onset. Experiments suggest that this EMH contained clonal populations of cells.;Southern blot analysis indicated, that c-myc and pal-1 were found to be re-arranged in 25% of the lymphomas in INK4a homozygous knockout, heterozygous and wild type mice. Thus, c-myc and pal-1 each perform at least one additional function in lymphomagenesis beyond those affected by the loss of p16 INK4a and P19ARF.;Genes commonly activated by Mo-MuLV in lymphomas, c-myc, pal-1, bmi-1 and pim-1, were not activated in severe EMH. I hypothesize that Mo-MuLV induced these clonal proliferations by insertional activation of a distinct set of oncogenes.;Finally, I examined oncogenes that were activated in T-cell lymphomas induced by SU retrovirus. Viral-host junction fragments were cloned from SL3-induced tumors. In one, the proviral insertion identified was located in the 5 '-untranslated sequences of LEF-1, a transcription factor that is part of the Wnt signal transduction pathway. The second SL3-tumor examined had only a single proviral integration that lies in an 11 kb-region that was cloned and sequenced. To date, no gene has been identified in that region. Screen of 100 independent tumors, showed no evidence that these were common viral integration sites.
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    https://yulib002.mc.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:9961339
    https://hdl.handle.net/20.500.12202/3871
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    • Albert Einstein College of Medicine: Doctoral Dissertations [1674]

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