Aberrant activation of NF-κB/Rel and AP-1 in adult T-cell leukemia

Adult T-cell leukemia (ATL) is a fatal T-lymphoproliferative disorder, and its development is associated with infection by human T-cell leukemia virus type I (HTLV-I). Several studies have suggested that aberrant transcription of cellular genes in HTLV-I infected cells plays a key role in the development of the disease. For instance, two transcription factors, nuclear factor kappa B (NF-kappaB)/Rel and activating protein-1 (AP-1), are transiently activated in normal T cells by growth-signals, whereas they are constitutively activated in HTLV-I infected T cells in vitro as well as in vivo. The HTLV-I oncoprotein Tax is responsible for the activation of NF-kappaB/Rel and AP-1 in HTLV-T transformed T-cell lines, and it induces a variety of cellular genes through NF-kappaB/Rel and AP-1. Unlike HTLV-I transformed T-cell lines, leukemic cells of ATL patients express extremely low levels of Tax protein, but NF-kappaB/Rel and AP-1 in leukemic cells are constitutively activated. Thus, the aberrant activation of NF-kappaB/Rel and AP-1 may be a key factor underlying the prolonged survival and proliferation of HTLV-I infected T cells both at the initial and late stages of leukemogenesis, although the mechanisms are different. In this review, we discuss the involvement of NF-kappaB/Rel and AP-1 in Tax-dependent and independent steps of leukemogenesis, and their role as potential therapeutic targets for treatment of ATL.