Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I

被引:215
作者
Hasegawa, H
Sawa, H
Lewis, MJ
Orba, Y
Sheehy, N
Yamamoto, Y
Ichinohe, T
Tsunetsugu-Yokota, Y
Katano, H
Takahashi, H
Matsuda, J
Sata, T
Kurata, T
Nagashima, K
Hall, WW [1 ]
机构
[1] Univ Coll Dublin, Sch Med & Med Sci, Ctr Res Infect Dis, Dublin 4, Ireland
[2] Natl Inst Infect Dis, Dept Pathol, Tokyo 2080011, Japan
[3] Hokkaido Univ, Res Ctr Zoonosis Control, Lab Mol & Cellular Pathol, Kita Ku, Sapporo, Hokkaido 0608338, Japan
[4] Hokkaido Univ, Res Ctr Zoonosis Control, Dept Mol Pathobiol, Kita Ku, Sapporo, Hokkaido 0608338, Japan
[5] 21st Century COE Program Zoonosis Control, Kita Ku, Sapporo, Hokkaido 0608338, Japan
[6] Univ Calif Los Angeles, Sch Med, Div Infect Dis, Los Angeles, CA 90095 USA
[7] Natl Inst Biomed Innovat, Osaka 5670085, Japan
[8] Natl Inst Infect Dis, Dept Immunol, Shinjuku Ku, Tokyo 1628640, Japan
关键词
D O I
10.1038/nm1389
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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收藏
页码:466 / 472
页数:7
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