Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

T-Cell Leukemia

Efficient engraftment of primary adult T-cell leukemia cells in newborn NOD/SCID/β2-microglobulinnull mice

Leukemia volume 19, pages 1384–1390 (2005)Cite this article

Abstract

Adult T-cell leukemia (ATL) develops via multiple oncogenic steps in human T-cell leukemia virus type I (HTLV-I) carriers. To better understand pathogenesis of ATL, we developed a novel xenogeneic engraftment model in which primary ATL cells are intravenously transplanted into neonatal nonobese diabetic (NOD)/severe-combined immunodeficiency (SCID)/β2-microglobulinnull (NOD/SCID/β2mnull) mice. Acute-type ATL cells engrafted in the peripheral blood and in the lymph nodes of recipients at a high efficiency. Engrafted ATL cells were dually positive for human CD4 and CD25, and displayed patterns of HTLV-I integration identical to those of donors by Southern blot analysis. These cells infiltrated into recipients' liver, and formed nodular lesions, recapitulating the clinical feature of each patient. In contrast, in smoldering-type ATL cases, multiple clones of ATL cells engrafted efficiently in NOD/SCID/β2mnull mice. When smoldering-type ATL cells were retransplanted into secondary NOD/SCID/β2mnull recipients, single HTLV-I-infected clones became predominant, suggesting that clones with dominant proliferative activity can be competitively selected in this xenogeneic system. Taken together, the NOD/SCID/β2mnull newborn system is useful to understand kinetics, metastasis, and disease progression of ATL in vivo.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

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

    CAS  PubMed  Google Scholar 

  2. Yoshida M, Miyoshi I, Hinuma Y . Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease. Proc Natl Acad Sci USA 1982; 79: 2031–2035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Seiki M, Hattori S, Hirayama Y, Yoshida M . Human adult T-cell leukemia virus: complete nucleotide sequence of the provirus genome integrated in leukemia cell DNA. Proc Natl Acad Sci USA 1983; 80: 3618–3622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tajima K, Kuroishi T . Estimation of rate of incidence of ATL among ATLV (HTLV-I) carriers in Kyushu, Japan. Jpn J Clin Oncol 1985; 15: 423–430.

    CAS  PubMed  Google Scholar 

  5. Shimoyama M . Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984–1987). Br J Haematol 1991; 79: 428–437.

    Article  CAS  PubMed  Google Scholar 

  6. Tsukasaki K, Tsushima H, Yamamura M, Hata T, Murata K, Maeda T et al. Integration patterns of HTLV-I provirus in relation to the clinical course of ATL: frequent clonal change at crisis from indolent disease. Blood 1997; 89: 948–956.

    CAS  PubMed  Google Scholar 

  7. Yamada Y, Tomonaga M, Fukuda H, Hanada S, Utsunomiya A, Tara M et al. A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemia-lymphoma: Japan Clinical Oncology Group Study 9303. Br J Haematol 2001; 113: 375–382.

    Article  CAS  PubMed  Google Scholar 

  8. Kami M, Hamaki T, Miyakoshi S, Murashige N, Kanda Y, Tanosaki R et al. Allogeneic haematopoietic stem cell transplantation for the treatment of adult T-cell leukaemia/lymphoma. Br J Haematol 2003; 120: 304–309.

    Article  PubMed  Google Scholar 

  9. Imada K, Takaori-Kondo A, Akagi T, Shimotohno K, Sugamura K, Hattori T et al. Tumorigenicity of human T-cell leukemia virus type I-infected cell lines in severe combined immunodeficient mice and characterization of the cells proliferating in vivo. Blood 1995; 86: 2350–2357.

    CAS  PubMed  Google Scholar 

  10. Phillips KE, Herring B, Wilson LA, Rickford MS, Zhang M, Goldman CK et al. IL-2Ralpha-directed monoclonal antibodies provide effective therapy in a murine model of adult T-cell leukemia by a mechanism other than blockade of IL-2/IL-2Ralpha interaction. Cancer Res 2000; 60: 6977–6984.

    CAS  PubMed  Google Scholar 

  11. Richard V, Lairmore MD, Green PL, Feuer G, Erbe RS, Albrecht B et al. Humoral hypercalcemia of malignancy: severe combined immunodeficient/beige mouse model of adult T-cell lymphoma independent of human T-cell lymphotropic virus type-1 tax expression. Am J Pathol 2001; 158: 2219–2228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dewan MZ, Terashima K, Taruishi M, Hasegawa H, Ito M, Tanaka Y et al. Rapid tumor formation of human T-cell leukemia virus type 1-infected cell lines in novel NOD-SCID/gammac(null) mice: suppression by an inhibitor against NF-kappaB. J Virol 2003; 77: 5286–5294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Feuer G, Zack JA, Harrington Jr WJ, Valderama R, Rosenblatt JD, Wachsman W et al. Establishment of human T-cell leukemia virus type I T-cell lymphomas in severe combined immunodeficient mice. Blood 1993; 82: 722–731.

    CAS  PubMed  Google Scholar 

  14. Kondo A, Imada K, Hattori T, Yamabe H, Tanaka T, Miyasaka M et al. A model of in vivo cell proliferation of adult T-cell leukemia. Blood 1993; 82: 2501–2509.

    CAS  PubMed  Google Scholar 

  15. Christianson SW, Greiner DL, Hesselton RA, Leif JH, Wagar EJ, Schweitzer IB et al. Enhanced human CD4+ T cell engraftment in beta2-microglobulin-deficient NOD-SCID mice. J Immunol 1997; 158: 3578–3586.

    CAS  PubMed  Google Scholar 

  16. Ishikawa F, Livingston AG, Wingard JR, Nishikawa S, Ogawa M . An assay for long-term engrafting human hematopoietic cells based on newborn NOD/SCID/beta2-microglobulin(null) mice. Exp Hematol 2002; 30: 488–494.

    Article  CAS  PubMed  Google Scholar 

  17. Kamihira S, Dateki N, Sugahara K, Yamada Y, Tomonaga M, Maeda T et al. Real-time polymerase chain reaction for quantification of HTLV-1 proviral load: application for analyzing aberrant integration of the proviral DNA in adult T-cell leukemia. Int J Hematol 2000; 72: 79–84.

    CAS  PubMed  Google Scholar 

  18. Tanaka T, Saito Y, Ueda M . Development and preliminary analysis for EBV clonality using non-RI probe. Rinsho Byori 2001; 49: 603–607.

    CAS  PubMed  Google Scholar 

  19. Motoi T, Uchiyama T, Uchino H, Ueda R, Araki K . Serum soluble interleukin-2 receptor levels in patients with adult T-cell leukemia and human T-cell leukemia/lymphoma virus type-I seropositive healthy carriers. Jpn J Cancer Res 1988; 79: 593–599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Imada K, Takaori-Kondo A, Sawada H, Imura A, Kawamata S, Okuma M et al. Serial transplantation of adult T cell leukemia cells into severe combined immunodeficient mice. Jpn J Cancer Res 1996; 87: 887–892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti JC, Lanzavecchia A et al. Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 2004; 304: 104–107.

    Article  CAS  PubMed  Google Scholar 

  22. Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T, Yoshimoto G et al. Development of functional human blood and immune systems in NOD/SCID/IL2 Receptor g chainnull mice. Blood 2005, (in press).

  23. Tsurumi H, Tani K, Tsuruta T, Shirato R, Matsudaira T, Tojo A et al. Adult T-cell leukemia developing during immunosuppressive treatment in a renal transplant recipient. Am J Hematol 1992; 41: 292–294.

    Article  CAS  PubMed  Google Scholar 

  24. Hoshida Y, Li T, Dong Z, Tomita Y, Yamauchi A, Hanai J et al. Lymphoproliferative disorders in renal transplant patients in Japan. Int J Cancer 2001; 91: 869–875.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Japan Society for the Promotion of Science (FI), NIH Grant A130389 (LDS), and Japan Ministry of Health, Labor, and Welfare (MH). We would like to thank Ms Miyamoto, Ms Funatsu, Ms Ikematsu, and Ms Baba for their excellent technical support. We are also grateful to Dr Hayashi, Dr Eto, Dr Kamimura, Dr Kato, Dr Takase, Dr Koyama, Dr Mitoma, Dr Tanimoto, and Dr Muta for helpful discussion and excellent clinical cares.

Author information

Authors and Affiliations

  1. Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medicine, Fukuoka, Japan

    N Kawano, F Ishikawa, K Shimoda, K Nagafuji, E Baba, S Yamasaki, H Gondo, T Otsuka & M Harada

  2. First Department of Internal Medicine, Ehime University School of Medicine, Ehime, Japan

    M Yasukawa

  3. Department of Infection and Immunology, SRL Inc., Hachioji, Japan

    T Tanaka

  4. First Department of Pathology, Fukuoka, Japan

    K Ohshima

  5. The Jackson Laboratory, Bar Harbor, ME, USA

    L D Shultz

  6. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, MA, USA

    K Akashi

  7. Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan

    T Miyamoto & K Akashi

Authors
  1. N Kawano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F Ishikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Shimoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Yasukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Nagafuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T Miyamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E Baba
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S Yamasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. H Gondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. T Otsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. K Ohshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. L D Shultz
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. K Akashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F Ishikawa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kawano, N., Ishikawa, F., Shimoda, K. et al. Efficient engraftment of primary adult T-cell leukemia cells in newborn NOD/SCID/β2-microglobulinnull mice. Leukemia 19, 1384–1390 (2005). https://doi.org/10.1038/sj.leu.2403829

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403829

Keywords

This article is cited by

Search

Advanced search

Quick links