Dual targeting of transformed and untransformed HTLV-1–infected T cells by DHMEQ, a potent and selective inhibitor of NF- B, 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 factorB (NFB) in the leukemic cells is essential for their growth and survival. Blocking NFB has been shown to be a potential strategy to treat ATL. We tested this approach using a novel NFB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), and also examined its application to chemoprevention by selective purging of the HTLV-1– infected cells. DHMEQ inhibited NFB activation in primary ATL cells and cell lines derived from them and induced apoptotic cell death. NFB 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 NFB is a potential molecular target for treatment and prevention of ATL. As a potent NFB inhibitor, DHMEQ is a promising compound allowing the translation of this strategy into clinical medicine. (Blood. 2005;106:2462-2471)