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  • Original Paper
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Vav-promoter regulated oncogenic fusion protein NPM-ALK in transgenic mice causes B-cell lymphomas with hyperactive Jun kinase

Oncogene volume 22, pages 7750–7761 (2003)Cite this article

Abstract

Anaplastic large-cell lymphoma is associated with a chromosomal translocation generating an oncogenic fusion protein: the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). We have generated several independent lines of human NPM-ALK transgenic mice using the haematopoietic cell-specific Vav promoter. Lymphomas develop in two transgenic lines in which the Vav promoter regulates NPM-ALK expression. The transgenic line with higher copy number displays an early-onset phenotype in which all mice succumb to aggressive lymph node tumours with intestinal involvement, whereas the second line displays late-onset tumour development in the spleen and/or liver. Lymphomas from both lines are phenotypically distinct and display B-lineage characteristics with aberrant coexpression of myeloid markers. The NPM-ALK kinase is active in primary tumour tissue and forms a multimeric complex with tyrosine-phosphorylated proteins, that is, Shc. Jun and ERK kinase activities in tumours are elevated by up to 30-fold and fivefold, respectively, in comparison with sIgM-stimulated primary B cells. The new transgenic models provide a system for investigating the oncogenic events mediated by NPM-ALK in situ and a physiologically relevant context for developing tyrosine kinase inhibitor therapies of potential use in the clinic.

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References

  • Bai RY, Dieter P, Peschel C, Morris SW and Duyster J . (1998). Mol. Cell. Biol., 18, 6951–6961.

  • Bai RY, Ouyang T, Miething C, Morris SW, Peschel C and Duyster J . (2000). Blood, 96, 4319–4327.

  • Benharroch D, MeguerianBedoyan Z, Lamant L, Amin C, Brugieres L, TerrierLacombe MJ, Haralambieva E, Pulford K, Pileri S, Morris SW, Mason DY and Delsol G . (1998). Blood, 91, 2076–2084.

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

  • Bost F, McKay R, Bost M, Potapova O, Dean NM and Mercola D . (1999). Mol. Cell. Biol., 19, 1938–1949.

  • Chan PK, Chan FY, Morris SW and Xie Z . (1997). Nucleic Acids Res., 25, 1225–1232.

  • Chiarle R, Gong JZ, Guasparri L, Pesci A, Cai J, Liu J, Simmons WJ, Dhall G, Howes J, Piva R and Inghirami G . (2003). Blood, 101, 1919–1927.

  • Corcoran AE, Riddell A, Krooshoop D and Venkitaraman AR . (1998). Nature, 391, 904–907.

  • Davis RJ . (2000). Cell, 103, 239–252.

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

  • Dickens M, Rogers JS, Cavavagh J, Raitano A, Xia Z, Halpern JR, Greenberg ME, Sawyers CL and Davis RJ . (1997). Science, 277, 693–696.

  • Duyster J, Bai RY and Morris SW . (2001). Oncogene, 20, 5623–5637.

  • Eferl R, Ricci B, Kenner L, Zenz R, David JP, Rath M and Wagner EF . (2003). Cell, 112, 181–192.

  • Ehlich A, Martin V, Muller W and Rajewsky K . (1994). Curr. Biol., 4, 573–583.

  • Falini B and Mason DY . (2002). Blood, 99, 409–426.

  • Falini B, Pulford K, Pucciarini A, Carbone A, De Wolf-Peeters C, Cordell J, Fizzotti M, Santucci A, Pelicci PG, Pileri S, Campo E, Ott G, Delsol G and Mason DY . (1999). Blood, 94, 3509–3515.

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

  • Gascoyne RD, Aoun P, Wu D, Chhanabhai M, Skinnider BF, Greiner TC, Morris SW, Connors JM, Vose JM, Viswanatha DS, Coldman A and Weisenburger DD . (1999). Blood, 93, 3913–3921.

  • Greenland C, Touriol C, Chevillard G, Morris SW, Bai R, Duyster J, Delsol G and Allouche M . (2001). Oncogene, 20, 7386–7397.

  • Hardy RR and Hayakawa K . (2001). Annu. Rev. Immunol., 19, 595–621.

  • Hariharan IK, Harris AW, Crawford M, Abud H, Webb E, Cory S and Adams JM . (1989). Mol. Cell. Biol., 9, 2798–2805.

  • Hess P, Pihan G, Sawyers CL, Flavell R and Davis RJ . (2002). Nat. Genet., 32, 201–205.

  • Hestdal K, Ruscetti FW, Ihle JN, Jacobsen SE, Dubois CM, Kopp WC, Longo DL and Keller JR . (1991). J. Immunol., 147, 22–28.

  • Iwahara T, Fujimoto J, Wen DZ, Cupples R, Bucay N, Arakawa T, Mori S, Ratzkin B and Yamamoto T . (1997). Oncogene, 14, 439–449.

  • Jaffe ES, Harris NL, Stein H and Vardiman JW (eds) (2001). Tumours of Haematopoietic and Lymphoid Tissue. IARC: Lyon.

    Google Scholar 

  • Johnson R, Spiegelman B, Hanahan D and Wisdon R . (1996). Mol. Cell. Biol., 16, 4504–4511.

  • Kanda M, Suzumiya J, Ohshima K, Okada M, Tamura K and Kikuchi M . (2001). Leuk. Lymphoma, 42, 639–647.

  • Katsura Y . (2002). Nat. Rev. Immunol., 2, 127–132.

  • Kuefer MU, Look AT, Tripp R, Behm FG, Pattengale PK and Morris SW . (1997). Blood, 90, 2901–2910.

  • Lamb JA, Ventura J-J, Hess P, Flavell RA and Davis RJ . (2003). Mol. Cell, 11, 1479–1489.

  • Kennedy NJ and Davis RJ . (2003). Cell Cycle, 2, 199–201.

  • Lanier LL and Hemperly JJ . (1995). Leucocyte Typing, V, 1398–1400.

  • Li YS, Wasserman R, Hayakawa K and Hardy RR . (1996). Immunity, 5, 527–535.

  • Maes B, Anastasopoulou A, Kluin-Nelemans JC, Teodorovic I, Achten R, Carbone A and De Wolf-Peeters C . (2001). Ann. Oncol., 12, 853–858.

  • Mason DY, Pulford KAF, Bischof D, Kuefer MU, Butler LH, Lamant L, Delsol G and Morris SW . (1998). Cancer Res., 58, 1057–1062.

  • 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 XL and Witte DP . (1997). Oncogene, 14, 2175–2188.

  • Morris SW, Naeve C, Mathew P, Kirstein MN, Cui XL and Witte DP . (1995). Blood, 86, 647.

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

  • Ogilvy S, Metcalf D, Gibson L, Bath ML, Harris AW and Adams JM . (1999a). Blood, 94, 1855–1863.

  • Ogilvy S, Metcalf D, Print CG, Bath ML, Harris AW and Adams JM . (1999b). Proc. Natl. Acad. Sci. USA, 96, 14943–14948.

  • Ogilvy S, Louis-Dit-Sully C, Cassady RL, Alexander DR and Holmes N . (2003). J. Immunol., 171, 1792–1800.

  • Onciu M, Behm FG, Downing JR, Shurtleff SA, Raimondi SC, Ma Z, Morris SW, Kennedy W, Jones SC and Sandlund JT . (2003). Blood, in press.

  • Peek Jr RM and Blaser MJ . (2002). Nat. Rev. Cancer, 2, 28–37.

  • Potapova O, Gorospe M, Dougherty RH, Dean NM, Gaarde WA and Holbrook NJ . (2000). Mol. Cell. Biol., 20, 1713–1722.

  • Pulford K, Lamant L, Morris SW, Butler LH, Wood KM, Stroud D, Delsol G and Mason DY . (1997). Blood, 89, 1394–1404.

  • Rabbitts TH . (1998). N. Engl. J. Med., 338, 192–194.

  • Sanderson D and Borset M . (2002). Ann. Hematol., 81, 125–135.

  • Schreiber M, Kolbus A, Piu F, Szabowski A, Mohle-Steinlein U, Tian J, Karin M, Angel P and Wagner EF . (1999). Genes Dev., 13, 607–619.

  • Sebestyen A, Berczi L, Mihalik R, Paku S, Matolcsy A and Kopper L . (1999). Br. J. Haematol, 104, 412–419.

  • Stewart M, Cameron E, Campbell M, McFarlane R, Toth S, Lang K, Onions D and Neil JC . (1993). Int. J. Cancer, 53, 1023–1030.

  • ten Boekel E, Melchers F and Rolink A . (1995). Int. Immunol., 7, 1013–1019.

  • Weisenburger DD, Anderson JR, Diebold J, Gascoyne RD, MacLennan KA, Muller-Hermelink HK, Nathwani BN, Ullrich F and Armitage JO . (2001). Am. J. Hematol., 67, 172–178.

  • Yang YM, Bost F, Charbono W, Dean N, McKay R, Rhim JS, Depatie C and Mercola D . (2003). Clin. Cancer Res., 9, 391–401.

  • Zhumabekov T, Corbella P, Tolaini M and Kioussis D . (1995). J. Immunol. Methods, 185, 133–140.

  • Zukerberg LR, Collins AB, Ferry JA and Harris NL . (1991). Am. J. Pathol., 139, 475–483.

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Acknowledgements

We thank Professor J Adams, Dr K Pulford, Dr A Corcoran and Professor S Morris for their generous gifts of reagents, Lill Holliday for her excellent animal husbandry, Geoff Morgan for help with the FACS analysis, and Christine Gascoine and Ailsa Rose for histological immunohistochemistry. We are also grateful to the Leukaemia Research Fund and to the Biotechnology and Biological Sciences Research Council for their financial support.

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Authors and Affiliations

  1. Laboratory of Lymphocyte Signalling and Development, Molecular Immunology Programme, The Babraham Institute, Babraham, Cambridge, CB2 4AT, UK

    Suzanne D Turner & Denis R Alexander

  2. Cancer Medicine Unit, St James University Hospital, Leeds, LS97TF, UK

    Reuben Tooze & Kenneth Maclennan

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  1. Suzanne D Turner
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  2. Reuben Tooze
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Correspondence to Denis R Alexander.

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Turner, S., Tooze, R., Maclennan, K. et al. Vav-promoter regulated oncogenic fusion protein NPM-ALK in transgenic mice causes B-cell lymphomas with hyperactive Jun kinase. Oncogene 22, 7750–7761 (2003). https://doi.org/10.1038/sj.onc.1207048

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