Interferon regulatory factor 4 as a therapeutic target in adult T-cell leukemia lymphoma

<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Adult T-cell leukemia lymphoma (ATLL) is a chemotherapy-resistant malignancy with a median survival of less than one year that will afflict between one hundred thousand and one million individuals worldwide who are currently infected with human T-cell leukemia virus type 1. Recurrent somatic mutations in host genes have exposed the T-cell receptor pathway through nuclear factor κB to interferon regulatory factor 4 (IRF4) as an essential driver for this malignancy. We sought to determine if IRF4 represents a therapeutic target for ATLL and to identify downstream effectors and biomarkers of IRF4 signaling in vivo.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>ATLL cell lines, particularly Tax viral oncoprotein-negative cell lines, that most closely resemble ATLL in humans, were sensitive to dose- and time-dependent inhibition by a next-generation class of IRF4 antisense oligonucleotides (ASOs) that employ constrained ethyl residues that mediate RNase H-dependent RNA degradation. ATLL cell lines were also sensitive to lenalidomide, which repressed IRF4 expression. Both ASOs and lenalidomide inhibited ATLL proliferation in vitro and in vivo<jats:italic>.</jats:italic> To identify biomarkers of IRF4-mediated CD4 + T-cell expansion in vivo<jats:italic>,</jats:italic> transcriptomic analysis identified several genes that encode key regulators of ATLL, including interleukin 2 receptor subunits α and β, KIT ligand, cytotoxic T-lymphocyte-associated protein 4, and thymocyte selection-associated high mobility group protein TOX 2.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>These data support the pursuit of IRF4 as a therapeutic target in ATLL with the use of either ASOs or lenalidomide.</jats:p> </jats:sec>