Aberrant Activation of Nf-kb/rel and Ap-1 in Adult T-cell Leukemia

摘要

Adult T-cell leukemia (ATL) is a fatal T4ymphoproliferative 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-L infected cells plays a key role In the development of the disease. For instance, two transcription factors, nuclear factor kappa B (NF-KB)/Rel and activating protein-1 (AP-1), are transiently activated in normal T cells by growth-signals, whereas they are con-stitutively 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-kB/ Rel and AP-1 in HTLV-I transformed T-cell lines, and it induces a variety of cellular genes through NF-KB/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-KB/Rel and AP-1 in leukemic cells are consti-tutively activated. Thus, the-aberrant activation of NF-KB/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 leukemogene-sis, although the mechanisms are different. In this review, we discuss the involvement of NF-KB/Rel and AP-1 in Tax-dependent and independent steps of leukemogenesis, and their role as potential therapeutic targets for treatment of ATL.