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


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.


  1. Matsuoka, M. Human T-cell leukemia virus type I and adult T-cell leukemia. Oncogene 22, 5131–5140 (2003).

    Article  CAS  Google Scholar 

  2. Takatsuki, K. et al. Clinical diversity in adult T-cell leukemia-lymphoma. Cancer Res. 45, 4644s–4645s (1985).

    CAS  PubMed  Google Scholar 

  3. Hattori, T. et al. Leukaemia of novel gastrointestinal T-lymphocyte population infected with HTLV-I. Lancet 337, 76–77 (1991).

    Article  CAS  Google Scholar 

  4. Suzushima, H. et al. Double-negative (CD4- CD8-) T cells from adult T-cell leukemia patients also have poor expression of the T-cell receptor alpha beta/CD3 complex. Blood 81, 1032–1039 (1993).

    CAS  PubMed  Google Scholar 

  5. Kamihira, S. et al. Unusual morphological features of adult T-cell leukemia cells with aberrant immunophenotype. Leuk. Lymphoma 12, 123–130 (1993).

    Article  CAS  Google Scholar 

  6. Suzushima, H., Asou, N., Hattori, T. & Takatsuki, K. Adult T-cell leukemia derived from S100 beta positive double-negative (CD4- CD8-) T cells. Leuk. Lymphoma 13, 257–262 (1994).

    Article  CAS  Google Scholar 

  7. Shimauchi, T., Hirokawa, Y. & Tokura, Y. Purpuric adult T-cell leukaemia/lymphoma: expansion of unusual CD4/CD8 double-negative malignant T cells expressing CCR4 but bearing the cytotoxic molecule granzyme B. Br. J. Dermatol. 152, 350–352 (2005).

    Article  CAS  Google Scholar 

  8. Yamada, Y. et al. Adult T-cell leukemia with atypical surface phenotypes: clinical correlation. J. Clin. Oncol. 3, 782–788 (1985).

    Article  CAS  Google Scholar 

  9. Ohata, J. et al. CD4/CD8 double-positive adult T-cell leukemia with preceding cytomegaloviral gastroenterocolitis. Int. J. Hematol. 69, 92–95 (1999).

    CAS  PubMed  Google Scholar 

  10. Ciminale, V. et al. Unusual CD4+CD8+ phenotype in a Greek patient diagnosed with adult T-cell leukemia positive for human T-cell leukemia virus type I (HTLV-I). Leuk. Res. 24, 353–358 (2000).

    Article  CAS  Google Scholar 

  11. Uchiyama, T., Yodoi, J., Sagawa, K., Takatsuki, K. & Uchino, H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood 50, 481–492 (1977).

    CAS  PubMed  Google Scholar 

  12. Yoshida, M. Multiple viral strategies of HTLV-1 for dysregulation of cell growth control. Annu. Rev. Immunol. 19, 475–496 (2001).

    Article  CAS  Google Scholar 

  13. Jeang, K.T., Giam, C.Z., Majone, F. & Aboud, M. Life, death, and tax: role of HTLV-I oncoprotein in genetic instability and cellular transformation. J. Biol. Chem. 279, 31991–31994 (2004).

    Article  CAS  Google Scholar 

  14. Sun, S.C. & Yamaoka, S. Activation of NF-kappaB by HTLV-I and implications for cell transformation. Oncogene 24, 5952–5964 (2005).

    Article  CAS  Google Scholar 

  15. Hall, W.W. & Fujisawa, M. Deregulation of cell-signalling pathways in HTLV-I infection. Oncogene 24, 5965–5975 (2005).

    Article  CAS  Google Scholar 

  16. Nerenberg, M., Hinrichs, S.H., Reynolds, R.K., Khoury, G. & Jay, G. The tat gene of human T-lymphotropic virus type 1 induces mesenchymal tumors in transgenic mice. Science 237, 1324–1329 (1987).

    Article  CAS  Google Scholar 

  17. Hinrichs, S.H., Nerenberg, M., Reynolds, R.K., Khoury, G. & Jay, G. A transgenic mouse model for human neurofibromatosis. Science 237, 1340–1343 (1987).

    Article  CAS  Google Scholar 

  18. Green, J.E., Hinrichs, S.H., Vogel, J. & Jay, G. Exocrinopathy resembling Sjogren's syndrome in HTLV-1 tax transgenic mice. Nature 341, 72–74 (1989).

    Article  CAS  Google Scholar 

  19. Iwakura, Y. et al. Induction of inflammatory arthropathy resembling rheumatoid arthritis in mice transgenic for HTLV-I. Science 253, 1026–1028 (1991).

    Article  CAS  Google Scholar 

  20. Green, J.E., Baird, A.M., Hinrichs, S.H., Klintworth, G.K. & Jay, G. Adrenal medullary tumors and iris proliferation in a transgenic mouse model of neurofibromatosis. Am. J. Pathol. 140, 1401–1410 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Grossman, W.J. et al. Development of leukemia in mice transgenic for the tax gene of human T-cell leukemia virus type I. Proc. Natl. Acad. Sci. USA 92, 1057–1061 (1995).

    Article  CAS  Google Scholar 

  22. Chaffin, K.E. et al. Dissection of thymocyte signaling pathways by in vivo expression of pertussis toxin ADP-ribosyltransferase. EMBO J. 9, 3821–3829 (1990).

    Article  CAS  Google Scholar 

  23. Wildin, R.S. et al. Developmental regulation of lck gene expression in T lymphocytes. J. Exp. Med. 173, 383–393 (1991).

    Article  CAS  Google Scholar 

  24. Mori, N. et al. Constitutive activation of NF-kappaB in primary adult T-cell leukemia cells. Blood 93, 2360–2368 (1999).

    CAS  PubMed  Google Scholar 

  25. Staal, F.J., Weerkamp, F., Langerak, A.W., Hendriks, R.W. & Clevers, H.C. Transcriptional control of T lymphocyte differentiation. Stem Cells 19, 165–179 (2001).

    Article  CAS  Google Scholar 

  26. Rezuke, W.N., Abernathy, E.C. & Tsongalis, G.J. Molecular diagnosis of B- and T-cell lymphomas: fundamental principles and clinical applications. Clin. Chem. 43, 1814–1823 (1997).

    CAS  PubMed  Google Scholar 

  27. Kannagi, M., Ohashi, T., Harashima, N., Hanabuchi, S. & Hasegawa, A. Immunological risks of adult T-cell leukemia at primary HTLV-I infection. Trends Microbiol. 12, 346–352 (2004).

    Article  CAS  Google Scholar 

  28. Noguchi, A. et al. Chromosomal mapping and zygosity check of transgenes based on flanking genome sequences determined by genomic walking. Exp. Anim. 53, 103–111 (2004).

    Article  CAS  Google Scholar 

  29. Dignam, J.D., Martin, P.L., Shastry, B.S. & Roeder, R.G. Eukaryotic gene transcription with purified components. Methods Enzymol. 101, 582–598 (1983).

    Article  CAS  Google Scholar 

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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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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).

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