pevonedistat and Leukemia--Prolymphocytic--T-Cell

Novel targeted agents used in therapy of lymphoid malignancies, such as inhibitors of B-cell receptor-associated kinases, are recognized to have complex immune-mediated effects. NEDD8-activating enzyme (NAE) has been identified as a tractable target in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. We and others have shown that pevonedistat (TAK-924), a small-molecule inhibitor of NAE, abrogates NF-κB signaling in malignant B cells. However, NF-κB pathway activity is indispensable in immune response, and T-cell function is altered in patients with CLL. Using T cells derived from patients with CLL, we demonstrate that although targeting NAE results in markedly differential expression of NF-κB-regulated genes and downregulation of interleukin (IL)-2 signaling during T-cell activation, T cells evade apoptosis. Meanwhile, NAE inhibition favorably modulates polarization of T cells in vitro, with decreased T

Topics: Antineoplastic Agents; Cell Line, Tumor; Cyclopentanes; Enzyme Inhibitors; Humans; Immunomodulation; Leukemia, Prolymphocytic, T-Cell; Lymphocyte Activation; Models, Biological; NEDD8 Protein; Pyrimidines; Receptors, Antigen, T-Cell; Signal Transduction; T-Lymphocytes; T-Lymphocytes, Helper-Inducer