Background 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. Results 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 . To identify biomarkers of IRF4-mediated CD4 + T-cell expansion in vivo , 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. Conclusions These data support the pursuit of IRF4 as a therapeutic target in ATLL with the use of either ASOs or lenalidomide.

中文翻译：

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干扰素调节因子 4 作为成人 T 细胞白血病淋巴瘤的治疗靶点

背景 成人 T 细胞白血病淋巴瘤 (ATLL) 是一种化疗耐药的恶性肿瘤，中位生存期不到一年，全球将有 10 万到 100 万人目前感染人类 T 细胞白血病病毒 1 . 宿主基因中反复发生的体细胞突变使 T 细胞受体通路通过核因子 κB 暴露于干扰素调节因子 4 (IRF4)，作为这种恶性肿瘤的重要驱动因素。我们试图确定 IRF4 是否代表 ATLL 的治疗靶点，并确定体内 IRF4 信号传导的下游效应物和生物标志物。结果 ATLL 细胞系，特别是 Tax 病毒癌蛋白阴性细胞系，与人类中的 ATLL 最相似，对下一代 IRF4 反义寡核苷酸 (ASO) 的剂量和时间依赖性抑制敏感，该类使用限制性乙基残基介导 RNase H 依赖性 RNA 降解。ATLL 细胞系也对抑制 IRF4 表达的来那度胺敏感。ASOs 和来那度胺在体外和体内均抑制 ATLL 增殖。为了确定 IRF4 介导的体内 CD4 + T 细胞扩增的生物标志物，转录组学分析确定了几个编码 ATLL 关键调节因子的基因，包括白细胞介素 2 受体亚基 α 和 β、KIT 配体、细胞毒性 T 淋巴细胞相关蛋白 4 和胸腺细胞选择相关的高迁移率群蛋白 TOX 2. 结论 这些数据支持使用 ASO 或来那度胺将 IRF4 作为 ATLL 的治疗靶点。