S1 File -

Human T-cell leukemia virus type I (HTLV-I) is an oncogenic virus whose infection can cause diverse diseases, most notably adult T-cell leukemia/lymphoma (ATL or ATLL), an aggressive and fatal malignancy of CD4 T cells. The oncogenic ability of HTLV-I is mostly attributed to the viral transcriptional transactivator Tax. Tax alone is sufficient to induce specific tumors in mice depending on the promotor used to drive Tax expression, thereby being used to understand HTLV-I tumorigenesis and model the tumor types developed in Tax transgenic mice. Tax exerts its oncogenic role predominantly by activating the cellular transcription factor NF-κB. Here, we report that genetic deletion of NF-κB1, the prototypic member of the NF-κB family, promotes adrenal medullary tumors but suppresses neurofibromas in mice with transgenic Tax driven by the HTLV-I Long Terminal Repeat (LTR) promoter. The adrenal tumors are derived from macrophages. Neoplastic macrophages also infiltrate the spleen and lymph nodes, causing splenomegaly and lymphadenopathy in mice. Nevertheless, the findings could be human relevant, because macrophages are important target cells of HTLV-I infection and serve as a virus reservoir in vivo. Moreover, the spleen, lymph nodes and adrenal glands are the most common sites of tumor cell infiltration in HTLV-I-infected patients. These data provide new mechanistic insights into the complex interaction between Tax and NF-κB, therefore improving our understanding of HTLV-I oncogenic pathogenesis. They also expand our knowledge and establish a new animal model of macrophage neoplasms and adrenal tumors.

人类T细胞白血病病毒I型（HTLV-I）是一种致癌病毒，其感染可引发多种疾病，其中最显著的是成人T细胞白血病/淋巴瘤（ATL或ATLL）——一种侵袭性且致命的CD4 T细胞恶性肿瘤。HTLV-I的致癌能力主要源自其病毒转录反式激活蛋白Tax。仅需单独表达Tax，即可根据驱动Tax表达的启动子类型在小鼠体内诱导特定肿瘤，因此该模型被用于研究HTLV-I的致癌机制，并模拟Tax转基因小鼠中出现的肿瘤类型。Tax主要通过激活细胞转录因子NF-κB来发挥致癌作用。本研究发现，在由HTLV-I长末端重复序列（LTR）启动子驱动Tax转基因的小鼠模型中，敲除NF-κB家族的经典成员NF-κB1，会促进肾上腺髓质肿瘤的发生，但抑制神经纤维瘤的形成。该肾上腺肿瘤起源于巨噬细胞。肿瘤性巨噬细胞还会浸润脾脏与淋巴结，导致小鼠出现脾肿大与淋巴结病。不过，该研究发现具有人类相关性：巨噬细胞是HTLV-I感染的重要靶细胞，并在体内作为病毒储存库。此外，脾脏、淋巴结与肾上腺是HTLV-I感染患者体内肿瘤细胞浸润的最常见部位。本研究数据为Tax与NF-κB之间的复杂相互作用提供了全新的机制视角，进而加深了我们对HTLV-I致癌发病机制的认知。该研究还拓展了相关领域的认知，并建立了巨噬细胞肿瘤与肾上腺肿瘤的新型动物模型。