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Abstract：
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.
摘要：
人类T细胞白血病病毒I型（HTLV-I）是一种致癌病毒，其感染可引起多种疾病，最值得注意的是成人T细胞白血病/淋巴瘤（ATL或ATLL），CD4T细胞的侵袭性和致命性恶性肿瘤。HTLV-I的致癌能力主要归因于病毒转录反式激活因子税。根据用于驱动Tax表达的启动子，仅Tax就足以在小鼠中诱导特定肿瘤，从而被用于理解HTLV-I肿瘤发生和在Tax转基因小鼠中发展的肿瘤类型的模型。Tax主要通过激活细胞转录因子NF-κB发挥其致癌作用。这里,我们报道了NF-κB家族的原型成员NF-κB1的遗传缺失，在HTLV-I长末端重复序列（LTR）启动子驱动的转基因Tax小鼠中，促进肾上腺髓质肿瘤，但抑制神经纤维瘤。肾上腺肿瘤来源于巨噬细胞。肿瘤巨噬细胞也渗入脾脏和淋巴结，引起小鼠脾肿大和淋巴结肿大。然而，这些发现可能与人类有关，因为巨噬细胞是HTLV-I感染的重要靶细胞，并在体内充当病毒库。此外，脾脏,淋巴结和肾上腺是HTLV-I感染患者肿瘤细胞浸润的最常见部位。这些数据为Tax和NF-κB之间的复杂相互作用提供了新的机制见解，因此，提高了我们对HTLV-I致癌发病机制的认识。他们还扩展了我们的知识，并建立了巨噬细胞肿瘤和肾上腺肿瘤的新动物模型。
