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 Paper
  • Published:

Overexpression of NPM–ALK induces different types of malignant lymphomas in IL-9 transgenic mice

Abstract

Anaplastic large-cell lymphoma (ALCL) comprises approximately 25% of all non-Hodgkin lymphomas (NHL) in children and young adults, and up to 15% of high-grade NHL in older patients. Over 50% of these tumours carry the translocation t(2;5)(p23;q35). The result of this translocation is the fusion of the nucleophosmin (NPM) gene to the anaplastic lymphoma kinase (ALK) gene. The resulting hybrid protein contains the ALK catalytic domain that consequently confers transforming potential, which contributes to the pathogenesis of ALCL. To further analyse the transforming activity in an animal model, a cDNA encoding the protein product, NPM–ALK, was inserted into the retrovirus vector pLXSN and transduced into mouse bone marrow progenitors. These cells were subsequently used in a bone marrow transplant with the aim of reconstituting the haematopoietic compartments of lethally irradiated recipients. IL-9 transgenic mice were chosen as the animal model system, because dysregulated expression of the IL-9 gene in transgenic mice results in the sporadic development of spontaneous thymic lymphomas. Moreover, IL-9 is known to be expressed in cases of human ALCL. We used 15 IL-9 transgenic mice and eight corresponding wild-type mice (FVB/N) and transplanted them with NPM/ALK infected bone marrow cells. Eight IL-9 transgenic mice, serving as a control group, received pLXSN (vector only)-infected marrow. Reconstituted mice developed NPM–ALK-positive lymphomas, including lymphoblastic lymphomas of T-cell type (T-LB), mature and immature plasmacytoma (PC), and plasmoblastic/anaplastic diffuse large-B-cell lymphoma after about 19–20 weeks. The combined overexpression of NPM–ALK and IL-9 led to the transformation of murine lymphoid cells with accelerated and enhanced development of T-LB in 46% of the mice, which only very rarely occurs in IL-9 transgenic mice only. Of the 15 animals, five (33%) developed plasmacytic/plasmoblastic neoplasms, of which the most aggressive tumours share many features with anaplastic/plasmoblastic diffuse large-B-cell lymphoma on the basis of morphology, a characteristic growth pattern and ALK expression.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Bischof D, Pulford K, Mason DY and Morris SW . (1997). Mol. Cell Biol., 17, 2312–2325.

  • Bittner C, Feller AC, Renauld JC, Lange K, Pietrzik R, Jenetzky C, Briese J, Gaiser T, Muller A, Wiedemann GJ, Van Snick J and Merz H . (2000). Lab. Invest., 80, 1523–1531.

  • Chomczynski P and Sacchi N . (1987). Anal. Biochem., 162, 156–159.

  • Delsol G, Lamant L, Mariame B, Pulford K, Dastugue N, Brousset P, Rigal-Huguet F, Al Saati T, Cerretti DP, Morris SW and Mason DY . (1997). Blood, 89, 1483–1490.

  • Demoulin JB and Renauld JC . (1998). Int. Rev. Immunol., 16, 345–364.

  • Dugas B, Renauld JC, Pene J, Bonnefoy JY, Peti-Frere C, Braquet P, Bousquet J, van Snick J and Mencia-Huerta JM . (1993). Eur. J. Immunol., 23, 1687–1692.

  • Fujimoto J, Shiota M, Iwahara T, Seki N, Satoh H, Mori S and Yamamoto T . (1996). Proc. Natl. Acad. Sci USA, 93, 4181–4186.

  • Graham FL and van der Eb AJ . (1973). Virology, 52, 456–467.

  • Kuefer MU, Look AT, Pulford K, Behm FG, Pattengale PK, Mason DY and Morris SW . (1997). Blood, 90, 2901–2910.

  • Ladanyi M . (1997). Cancer Surv., 30, 59–75.

  • Lawrence B, Perez-Atayde A, Hibbard MK, Rubin BP, Dal Cin P, Pinkus JL, Pinkus GS, Xiao S, Yi ES, Fletcher CD and Fletcher JA . (2000). Am. J. Pathol., 157, 377–384.

  • Le Beau MM, Bitter MA, Larson RA, Doane LA, Ellis ED, Franklin WA, Rubin CM, Kadin ME and Vardiman JW . (1989). Leukemia, 3, 866–870.

  • Look AT . (1997). Science, 278, 1059–1064.

  • Maes B, Vanhentenrijk V, Wlodarska I, Cools J, Peeters B, Marynen P and Wolf-Peeters C . (2001). Am. J. Pathol., 158, 2185–2193.

  • Markowitz D, Goff S and Bank A . (1988). J. Virol., 62, 1120–1124.

  • Merz H, Houssiau FA, Orscheschek K, Renauld JC, Fliedner A, Herin M, Noel H, Kadin M, Mueller-Hermelink HK and Van Snick J . (1991). Blood, 78, 1311–1317.

  • Miller AD and Rosman GJ . (1989). Biotechniques, 7, 980–986, 989.

  • Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL and Look AT . (1994). Science, 263, 1281–1284.

  • Morris SW, Naeve C, Mathew P, James PL, Kirstein MN, Cui X and Witte DP . (1997). Oncogene, 14, 2175–2188.

  • Morris SW, Xue L, Ma Z and Kinney MC . (2001). Br. J. Haematol., 113, 275–295.

  • Petit-Frere C, Dugas B, Braquet P and Mencia-Huerta JM . (1993). Immunology, 79, 146–151.

  • Plowman GD, Sudarsanam S, Bingham J, Whyte D and Hunter T . (1999). Proc. Nat. Acad. Sci. USA, 96, 13603–13610.

  • Rabbitts TH . (2001). Oncogene, 20, 5763–5777.

  • Renauld JC, van der LN, Vink A, van Roon M, Godfraind C, Warnier G, Merz H, Feller A, Berns A and Van Snick J . (1994). Oncogene, 9, 1327–1332.

  • Renauld JC, Vink A, Louahed J and Van Snick J . (1995). Blood, 85, 1300–1305.

  • Robinson DR, Wu YM and Lin SF . (2000). Oncogene, 19, 5548–5557.

  • Taketo M, Schroeder AC, Mobraaten LE, Gunning KB, Hanten G, Fox RR, Roderick TH, Stewart CL, Lilly F, Hansen CT and Overbeek PA . (1991). Proc. Natl. Acad. Sci USA, 88, 2065–2069.

  • Tort F, Pinyol M, Pulford K, Roncador G, Hernandez L, Nayach I, Kluin-Nelemans HC, Kluin P, Touriol C, Delsol G, Mason D and Campo E . (2001). Lab. Invest., 81, 419–426.

  • Touriol C, Greenland C, Lamant L, Pulford K, Bernard F, Rousset T, Mason DY and Delsol G . (2000). Blood, 95, 3204–3207.

  • Uckert W, Pedersen L and Günzburg W . (2000). In: Walther W and Stein U (eds). Methods in Molecular Medicine, Vol. 35: Gene Therapy: Methods and Protocols. Human Press: Totowa, NJ. pp. 271–281.

  • Uyttenhove C, Druez C, Renauld JC, Herin M, Noel H and Van-Snick J . (1991). J. Exp. Med., 173, 519–522.

  • Vink A, Renauld JC, Warnier G and Van Snick J . (1993). Eur. J. Immunol., 23, 1134–1138.

  • Wellmann A, Doseeva V, Butscher W, Raffeld M, Fukushima P, Stetler-Stevenson M and Gardner K . (1997). FASEB J., 11, 965–972.

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Karin Lange.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lange, K., Uckert, W., Blankenstein, T. et al. Overexpression of NPM–ALK induces different types of malignant lymphomas in IL-9 transgenic mice. Oncogene 22, 517–527 (2003). https://doi.org/10.1038/sj.onc.1206076

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206076

Keywords

This article is cited by

Search

Quick links