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Contribution of Inducible Nitric Oxide Synthase to the Transformation of HTLV-1 Infected CD4+ T-Cells

Hicham H. Baydoun and Lee Ratner

The Human T-cell Leukemia Virus type 1 (HTLV-1), is the first retrovirus associated with a human cancer. HTLV-1 is the causative agent of an aggressive and fatal malignancy of CD4+ T lymphocytes known as Adult T-cell Leukemia lymphoma (ATLL). Since the discovery of the virus in 1980, intensive investigations have been undertaken to determine how HTLV-1 drives the transformation process in infected cells. This is because the oncogenic features of HTLV-1 make it an excellent tool to dissect the molecular pathways involved in cancer development. More important, HTLV-1 induced leukemia is a typical inflammation-mediated malignancy with constitutive activation of the NF-kB pathway, which is also a critical determinant in many other cancers. How NF-kB contributes to the leukemogenic process is not completely defined. We recently demonstrated that the NF-kB pathway induces the expression of inducible nitric oxide synthase (iNOS) in HTLV-1 induced leukemia. iNOS enzymatically generates nitric oxide, which is an oxidative and nitrosative agent of DNA and protein. Nitric oxide was found to be associated with a large number of DNA Double Strand Breaks (DSBs) in HTLV-1 transformed cells. Here, we will review the major effects of nitric oxide on HTLV-1 induced leukemia.