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

Nature Medicine volume 12, pages 466–472 (2006)Cite this article

Abstract

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-κB. 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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Figure 1: Construction of the Tax transgene and Tax mRNA expression in transgenic mice.
Figure 2: Pathological findings of T-cell lymphoma and leukemia in Tax transgenic mice.
Figure 3: Gross and histological findings of lymphoma in SCID mice at 28 d after intradermal injection of lymphomatous cells from Tax transgenic mice.
Figure 4: Flow cytometry analysis of cell-surface and intracellular markers in lymphomatous cells.
Figure 5: EMSAs showing activation of NF-κB in lymphomatous cells.

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Acknowledgements

We thank Y. Sato and E. Tao for their technical assistance. We also thank O. Suzuki, T. Suzuki, M. Moriyama, K. Iwabuchi and Y. Misaki for advice. Y.O. is a Research Fellow of the Japanese Society for the Promotion of Science. These studies were supported by the Japanese Foundation for AIDS Prevention, Core Research for Evolutional Science and Technology (CREST), Ministry of Education and Culture, Japan and the National Virus Reference Laboratory, University College Dublin, Ireland.

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Author notes

  1. Hideki Hasegawa and Hirofumi Sawa: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo, 208-0011, Japan

    Hideki Hasegawa, Takeshi Ichinohe, Harutaka Katano, Hidehiro Takahashi, Tetsutaro Sata & Takeshi Kurata

  2. Centre for Research in Infectious Diseases, School of Medicine & Medical Science, University College Dublin, Belfield, Dublin, 4, Ireland

    Hideki Hasegawa, Martha J Lewis, Noreen Sheehy & William W Hall

  3. Laboratory of Molecular & Cellular Pathology, Hokkaido University Research Center for Zoonosis Control and 21st Century COE Program for Zoonosis Control, N18 W9, Kita-ku, 060-8638, Sapporo, Japan

    Hirofumi Sawa, Yasuko Orba & Kazuo Nagashima

  4. Department of Molecular Pathobiology, Hokkaido University Research Center for Zoonosis Control and 21st Century COE Program for Zoonosis Control, N18 W9, Kita-ku, 060-8638, Sapporo, Japan

    Hirofumi Sawa

  5. Division of Infectious Diseases, UCLA School of Medicine, 10833 Le Conte Avenue, CHS 37-121, Los Angeles, 90095, California, USA

    Martha J Lewis

  6. National Institute of Biomedical Innovation, Ibaraki-shi, 567-0085, Osaka, Japan

    Yoshie Yamamoto & Junichiro Matsuda

  7. Department of Immunology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, 162-8640, Tokyo, Japan

    Yasuko Tsunetsugu-Yokota

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  1. Hideki Hasegawa
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Correspondence to William W Hall.

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Supplementary information

Supplementary Fig. 1

Transcription factor profiling in SCID splenic lymphomatous cells (SCID-L) nuclear extracts. (PDF 460 kb)

Supplementary Methods (PDF 51 kb)

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Hasegawa, H., Sawa, H., Lewis, M. et al. Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I. Nat Med 12, 466–472 (2006). https://doi.org/10.1038/nm1389

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