Dual targeting of transformed and untransformed HTLV-1-infected T cells by DHMEQ, a potent and selective inhibitor of NF-κB, as a strategy for chemoprevention and therapy of adult T-cell leukemia

Human T-cell leukemia virus type I (HTLV-1) causes adult T-cell leukemia (ATL), a fatal T-cell leukemia resistant to chemotherapy, after more than 50 years of clinical latency from transmission through breast-feeding. Polyclonal expansion of virus-infected T cells predisposes them to transformation. Constitutive activation of nuclear factor-kappa B (NF-kappa B) in the leukemic cells is essential for their growth and survival. Blocking NF-kappa B has been shown to be a potential strategy to treat ATL. We tested this approach using a novel NF-kappa B inhibitor, dehydroxymethyl-epoxyquinomicin (DHMEQ), and also examined its application to chemoprevention by selective purging of the HTLV-1-infected cells. DHMEQ inhibited NF-kappa B activation in primary ATL cells and cell lines derived from them and induced apoptotic cell death. NF-kappa B inhibition downregulated expression of genes involved in antiapoptosis or cell-cycle progression. DHMEQ protected severe combined immunodeficiency (SCID) mice inoculated with HTLV-1-transformed cells from death. In addition, DHMEQ selectively targeted HTLV-1 -infected cells in the peripheral blood of virus carriers in vitro, resulting in a decreased number of infected cells. We conclude that NF-kappa B is a potential molecular target for treatment and prevention of ATL. As a potent NF-kappa B inhibitor, DHMEQ is a promising compound allowing the translation of this strategy into clinical medicine.