Abstract
The human T cell leukemia/lymphotropic virus-1 (HTLV-I) is the etiologic agent of adult T cell leukemia (ATL), an aggressive and fatal leukemia of CD4+ T lymphocytes. Interferon regulatory factor-4 (IRF-4) was shown previously to be constitutively expressed in T cells infected with HTLV-1. In this study, we investigated the role of IRF-4 gene regulation in the context of HTLV-1 infection using gene array technology and IRF-4 expressing T cells. Many potential IRF-4 regulated genes were identified, the vast majority of which were repressed by IRF-4 expression. Cyclin B1, a G2-M checkpoint protein identified as an IRF-4 repressed gene in the array, was further characterized in the context of HTLV-1 infection. All HTLV-1 infected cell lines and ATL patient lymphocytes demonstrated a dramatic decrease in cyclin B1 levels; subsequent analysis of the cyclin B1 promoter identified two sites important in IRF-4 binding and repression of cyclin B1 expression. Furthermore, IRF-4-mediated repression of cyclin B1 led to a significant decrease in CDC2 kinase activity in HTLV-1 infected T cells. IRF-4 expression in HTLV-1 infected T cells also downregulated other genes implicated in the mitotic checkpoint as well as genes involved in actin cytoskeletal rearrangement, DNA repair, apoptosis, metastasis and immune recognition. Several of the identified genes are dysregulated in ATL and may provide important mechanistic information concerning pathways critical to the emergence of ATL.
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Acknowledgements
The authors wish to thank Dr Harinder Singh at the Howard Hughes Institute, University of Chicago for IRF-4, Dr William R Taylor, at the Lerner Research Institute, Cleveland Clinic Foundation for cyclin B1 promoter deletion constructs, as well as the many researchers who provided us with antibodies and expression constructs (see Materials and methods). We also thank the members of the Molecular Oncology Group, Lady Davis Institute, McGill University for helpful discussions. This research was supported by grants from the National Cancer Institute with funds from the Canadian Cancer Society and the CIHR of Canada. Y Mamane was supported by CIHR. N Grandvaux and S Sharma are supported by FRSQ fellowship and studentship, respectively. R Lin is supported in part by a Fraser Monat McPherson Fellowship from McGill University and J Hiscott by a CIHR Senior Scientist award recipient.
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Mamane, Y., Grandvaux, N., Hernandez, E. et al. Repression of IRF-4 target genes in human T cell leukemia virus-1 infection. Oncogene 21, 6751–6765 (2002). https://doi.org/10.1038/sj.onc.1205843
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DOI: https://doi.org/10.1038/sj.onc.1205843
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