Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I
Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I
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DOI：
10.1038/nm1389
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发表时间：
2006-04-01
期刊：
影响因子：
82.9
通讯作者：
Hall, WW
中科院分区：
文献类型：
--
作者：
Hasegawa, H;Sawa, H;Hall, WW
成人T细胞白血病-淋巴瘤（ATLL）是由人类嗜T淋巴细胞病毒I型（HTLV-I）感染引起的一组T细胞恶性肿瘤。虽然ATLL的发病机制仍然不完全清楚，病毒调节蛋白Tax是参与细胞转化的中心。在这里，我们描述了一代HTLV-I税收转基因小鼠使用LCK近端启动子限制转基因表达发育胸腺细胞。经过长时间的潜伏期，转基因小鼠发展为弥漫性大细胞淋巴瘤和白血病，具有急性ATLL的临床、病理和免疫学特征。转基因小鼠功能性免疫功能低下，他们开发机会性感染。在移植转基因小鼠的淋巴瘤细胞后，SCID小鼠也迅速发展成暴发性疾病。流式细胞仪检测显示细胞内CD 4、CD 8均为阴性，CD 44、CD 25和胞浆CD 3均为阳性。该表型是胸腺来源的前T细胞表型的指示，并且疾病发展与NF-κ B的组成性激活相关。我们的模型准确地再现了人类疾病，并将为分析转化中的分子事件和开发新的治疗方法提供工具。
Adult T-cell leukemia-lymphoma (ATLL) is a group of T-cell malignancies caused by infection with human T-lymphotropic virus type I (HTLV-I). Although the pathogenesis of ATLL remains incompletely understood, the viral regulatory protein Tax is centrally involved in cellular transformation. Here we describe the generation of HTLV-I Tax transgenic mice using the Lck proximal promoter to restrict transgene expression to developing thymocytes. After prolonged latency periods, transgenic mice developed diffuse large-cell lymphomas and leukemia with clinical, pathological and immunological features characteristic of acute ATLL. Transgenic mice were functionally immunocompromised and they developed opportunistic infections. Fulminant disease also developed rapidly in SCID mice after engraftment of lymphomatous cells from transgenic mice. Flow cytometry showed that the cells were CD4(-) and CD8(-), but CD44(+), CD25(+) and cytoplasmic CD3(+). This phenotype is indicative of a thymus-derived pre-T-cell phenotype, and disease development was associated with the constitutive activation of NF-kappa B. Our model accurately reproduces human disease and will provide a tool for analysis of the molecular events in transformation and for the development of new therapeutics.