On the TRAIL of a new therapy for leukemia

The cytokine TRAIL (tumor necrosis factor alpha-related apoptosis-inducing ligand) as well as agonistic antibodies that bind to the TRAIL receptors, death receptor 4 (DR4) and DR5, are undergoing preclinical and early clinical evaluation as potential therapeutic agents for a variety of hematological and non-hematological malignancies. Here, we briefly review the normal biological function of TRAIL, the mechanism of cytotoxicity of TRAIL receptor ligands, and their effects on normal myeloid progenitors, myelodysplastic marrow and leukemic cells, including acute myelogenous leukemia (AML) and chronic lymphocytic leukemia (CLL), in vitro. Recent observations suggesting that DR4 is the predominant receptor for the cytotoxic effects of TRAIL in CLL and that histone deacetylase inhibitors synergize with TRAIL in CLL in vitro are described and discussed. Collectively, the reviewed studies not only illustrate the potential therapeutic usefulness of TRAIL and the agonistic antibodies, but also highlight the need for additional preclinical evaluation of these agents.