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What have we learnt from mouse models of NPM-ALK-induced lymphomagenesis?

Leukemia volume 19, pages 1128–1134 (2005)Cite this article

Abstract

The nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is generated as a t(2;5) chromosomal breakpoint product, typically in CD30+ anaplastic large cell lymphomas. Activation of the NPM-ALK tyrosine kinase by NPM dimerisation causes autophosphorylation at multiple tyrosine residues and the consequent recruitment of a ‘signalosome’ that couples the fusion protein to pathways regulating mitogenesis and apoptosis. This review focuses on recent advances in our understanding of the transforming signals induced by this fusion protein in mouse models.

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References

  1. Drexler HG, Gignac SM, von Wasielewski R, Werner M, Dirks WG . Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas. Leukemia 2000; 14: 1533–1559.

    Article  CAS  PubMed  Google Scholar 

  2. Duyster J, Bai RY, Morris SW . Translocations involving anaplastic lymphoma kinase (ALK). Oncogene 2001; 20: 5623–5637.

    Article  CAS  PubMed  Google Scholar 

  3. Ladanyi M . The NPM/ALK gene fusion in the pathogenesis of anaplastic large cell lymphoma. Cancer Surv 1997; 30: 59–75.

    CAS  PubMed  Google Scholar 

  4. Pulford K, Morris SW, Turturro F . Anaplastic lymphoma kinase proteins in growth control and cancer. J Cell Physiol 2004; 199: 330–358.

    Article  CAS  PubMed  Google Scholar 

  5. Stein H, Mason DY, Gerdes J, O'Connor N, Wainscoat J, Pallesen G et al. The expression of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood 1985; 66: 848–858.

    CAS  PubMed  Google Scholar 

  6. Kaneko Y, Frizzera G, Edamura S, Maseki N, Sakurai M, Komada et al. A novel translocation, t(2;5)(p23;q35), in childhood phagocytic large T-cell lymphoma mimicking malignant histiocytosis. Blood 1989; 73: 806–813.

    CAS  PubMed  Google Scholar 

  7. Mason DY, Bastard C, Rimokh R, Dastugue N, Huret JL, Kristoffersson U et al. CD30-positive large cell lymphomas (‘Ki-1 lymphoma’) are associated with a chromosomal translocation involving 5q35. Br J Haematol 1990; 74: 161–168.

    Article  CAS  PubMed  Google Scholar 

  8. Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 1994; 263: 1281–1284.

    Article  CAS  PubMed  Google Scholar 

  9. Rimokh R, Magaud JP, Berger F, Samarut J, Coiffier B, Germain D et al. A translocation involving a specific breakpoint (q35) on chromosome 5 is characteristic of anaplastic large cell lymphoma (‘Ki-1 lymphoma’). Br J Haematol 1989; 71: 31–36.

    Article  CAS  PubMed  Google Scholar 

  10. Shiota M, Fujimoto J, Semba T, Satoh H, Yamamoto T, Mori, S . Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3. Oncogene 1994; 9: 1567–1574.

    CAS  PubMed  Google Scholar 

  11. Shiota M, Nakamura S, Ichinohasama R, Abe M, Akagi T, Takeshita M et al. Anaplastic large cell lymphomas expressing the novel chimeric protein p80NPM/ALK: a distinct clinicopathologic entity. Blood 1995; 86: 1954–1960.

    CAS  PubMed  Google Scholar 

  12. Gascoyne RD, Aoun P, Wu D, Chhanabhai M, Skinnider BF, Greiner TC et al. Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma. Blood 1999; 93: 3913–3921.

    CAS  PubMed  Google Scholar 

  13. Delsol G, Lamant L, Mariame B, Pulford K, Dastugue N, Brousset P et al. A new subtype of large B-cell lymphoma expressing the ALK kinase and lacking the 2; 5 translocation. Blood 1997; 89: 1483–1490.

    CAS  PubMed  Google Scholar 

  14. Adam P, Katzenberger T, Seeberger H, Gattenlohner S, Wolf J, Steinlein C et al. A case of a diffuse large B-cell lymphoma of plasmablastic type associated with the t(2;5)(p23;q35) chromosome translocation. Am J Surg Pathol 2003; 27: 1473–1476.

    Article  PubMed  Google Scholar 

  15. Gatter KM, Rader A, Braziel RM . Fine-needle aspiration biopsy of anaplastic large cell lymphoma, small cell variant with prominent plasmacytoid features: case report. Diagn Cytopathol 2002; 26: 113–116.

    Article  PubMed  Google Scholar 

  16. Onciu M, Behm FG, Downing JR, Shurtleff SA, Raimondi SC, Ma Z et al. ALK-positive plasmablastic B-cell lymphoma with expression of the NPM-ALK fusion transcript: report of 2 cases. Blood 2003; 102: 2642–2644.

    Article  CAS  PubMed  Google Scholar 

  17. De Paepe P, Baens M, van Krieken H, Verhasselt B, Stul M, Simons A et al. ALK activation by the CLTC-ALK fusion is a recurrent event in large B-cell lymphoma. Blood 2003; 102: 2638–2641.

    Article  CAS  PubMed  Google Scholar 

  18. Gascoyne RD, Lamant L, Martin-Subero JI, Lestou VS, Harris NL, Muller-Hermelink HK et al. ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases. Blood 2003; 102: 2568–2573.

    Article  CAS  PubMed  Google Scholar 

  19. Kuefer MU, Look AT, Pulford K, Behm FG, Pattengale PK, Mason DY et al. Retrovirus-mediated gene transfer of NPM-ALK causes lymphoid malignancy in mice. Blood 1997; 90: 2901–2910.

    CAS  PubMed  Google Scholar 

  20. Miething C, Grundler R, Fend F, Hoepfl J, Mugler C, von Schilling C et al. The oncogenic fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) induces two distinct malignant phenotypes in a murine retroviral transplantation model. Oncogene 2003; 22: 4642–4647.

    Article  CAS  PubMed  Google Scholar 

  21. Lange K, Uckert W, Blankenstein T, Nadrowitz R, Bittner C, Renauld JC et al. Overexpression of NPM-ALK induces different types of malignant lymphomas in IL-9 transgenic mice. Oncogene 2003; 22: 517–527.

    Article  CAS  PubMed  Google Scholar 

  22. Chiarle R, Gong JZ, Guasparri I, Pesci A, Cai J, Liu J et al. NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors. Blood 2003; 101: 1919–1927.

    Article  CAS  PubMed  Google Scholar 

  23. Turner SD, Tooze R, Maclennan K, Alexander DR . Vav-promoter regulated oncogenic fusion protein NPM-ALK in transgenic mice causes B-cell lymphomas with hyperactive Jun kinase. Oncogene 2003; 22: 7750–7761.

    Article  CAS  PubMed  Google Scholar 

  24. Pfeifer W, Levi E, Petrogiannis-Haliotis T, Lehmann L, Wang Z, Kadin ME . A murine xenograft model for human CD30+ anaplastic large cell lymphoma. Successful growth inhibition with an anti-CD30 antibody (HeFi-1). Am J Pathol 1999; 155: 1353–1359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Heisterkamp N, Jenster G, Kioussis D, Pattengale PK, Groffen J . Human bcr-abl gene has a lethal effect on embryogenesis. Transgenic Res 1991; 1: 45–53.

    Article  CAS  PubMed  Google Scholar 

  26. Ogilvy S, Metcalf D, Gibson L, Bath ML, Harris AW, Adams, JM . Promoter elements of vav drive transgene expression in vivo throughout the hematopoietic compartment. Blood 1999; 94: 1855–1863.

    CAS  PubMed  Google Scholar 

  27. Colombo E, Marine JC, Danovi D, Falini B, Pelicci PG . Nucleophosmin regulates the stability and transcriptional activity of p53. Nat Cell Biol 2002; 4: 529–533.

    Article  CAS  PubMed  Google Scholar 

  28. Kurki S, Peltonen K, Latonen L, Kiviharju TM, Ojala PM, Meek D, Laiho M . Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cancer Cell 2004; 5: 465–475.

    Article  CAS  PubMed  Google Scholar 

  29. Horie R, Watanabe M, Ishida T, Koiwa T, Aizawa S, Itoh K et al. The NPM-ALK oncoprotein abrogates CD30 signaling and constitutive NF-kappaB activation in anaplastic large cell lymphoma. Cancer Cell 2004; 5: 353–364.

    Article  CAS  PubMed  Google Scholar 

  30. Maes B, Vanhentenrijk V, Wlodarska I, Cools J, Peeters B, Marynen P et al. The NPM-ALK and the ATIC-ALK fusion genes can be detected in non-neoplastic cells. Am J Pathol 2001; 158: 2185–2193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pulford K, Lamant L, Morris SW, Butler LH, Wood KM, Stroud D et al. Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1. Blood 1997; 89: 1394–1404.

    CAS  PubMed  Google Scholar 

  32. Trumper L, Pfreundschuh M, Bonin FV, Daus H . Detection of the t(2;5)-associated NPM/ALK fusion cDNA in peripheral blood cells of healthy individuals. Br J Haematol 1998; 103: 1138–1144.

    Article  CAS  PubMed  Google Scholar 

  33. Renauld JC, van der Lugt N, Vink A, van Roon M, Godfraind C, Warnier G et al. Thymic lymphomas in interleukin 9 transgenic mice. Oncogene 1994; 9: 1327–1332.

    CAS  PubMed  Google Scholar 

  34. Demoulin JB, Renauld JC . Interleukin 9 and its receptor: an overview of structure and function. Int Rev Immunol 1998; 16: 345–364.

    Article  CAS  PubMed  Google Scholar 

  35. Miething C, Grundler R, Mugler C, Peschel C, Dyuster J . A new method of retroviral lineage specific expression utilizing the Cre/Lox system induces T-lymphoid malignancy in a mouse model of ALCL. Blood 2005; 104: 248.

    Google Scholar 

  36. Bai RY, Ouyang T, Miething C, Morris SW, Peschel C, Duyster J . Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. Blood 2000; 96: 4319–4327.

    CAS  PubMed  Google Scholar 

  37. Coluccia AM, Perego S, Cleris L, Gunby RH, Passoni L, Marchesi E et al. Bcl-XL down-regulation suppresses the tumorigenic potential of NPM/ALK in vitro and in vivo. Blood 2004; 103: 2787–2794.

    Article  CAS  PubMed  Google Scholar 

  38. Mathas S, Hinz M, Anagnostopoulos I, Krappmann D, Lietz A, Jundt F et al. Aberrantly expressed c-Jun and JunB are a hallmark of Hodgkin lymphoma cells, stimulate proliferation and synergize with NF-kappa B. EMBO J 2002; 21: 4104–4113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nieborowska-Skorska M, Slupianek A, Xue L, Zhang Q, Raghunath PN, Hoser G et al. Role of signal transducer and activator of transcription 5 in nucleophosmin/anaplastic lymphoma kinase-mediated malignant transformation of lymphoid cells. Cancer Res 2001; 61: 6517–6523.

    CAS  PubMed  Google Scholar 

  40. Slupianek A, Nieborowska-Skorska M, Hoser G, Morrione A, Majewski M, Xue L et al. Role of phosphatidylinositol 3-kinase-Akt pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis. Cancer Res 2001; 61: 2194–2199.

    CAS  PubMed  Google Scholar 

  41. Souttou B, Carvalho NB, Raulais D, Vigny M . Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway. J Biol Chem 2001; 276: 9526–9531.

    Article  CAS  PubMed  Google Scholar 

  42. Zamo A, Chiarle R, Piva R, Howes J, Fan Y, Chilosi M et al. Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death. Oncogene 2002; 21: 1038–1047.

    Article  CAS  PubMed  Google Scholar 

  43. Zhang Q, Raghunath PN, Xue L, Majewski M, Carpentieri DF, Odum N et al. Multilevel dysregulation of STAT3 activation in anaplastic lymphoma kinase-positive T/null-cell lymphoma. J Immunol 2002; 168: 466–474.

    Article  CAS  PubMed  Google Scholar 

  44. Crockett DK, Lin Z, Elenitoba-Johnson KS, Lim MS . Identification of NPM-ALK interacting proteins by tandem mass spectrometry. Oncogene 2004; 23: 2617–2629.

    Article  CAS  PubMed  Google Scholar 

  45. Bai RY, Dieter P, Peschel C, Morris SW, Duyster J . Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-gamma to mediate its mitogenicity. Mol Cell Biol 1998; 18: 6951–6961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cussac D, Greenland C, Roche S, Bai RY, Duyster J, Morris SW et al. Nucleophosmin-anaplastic lymphoma kinase of anaplastic large-cell lymphoma recruits, activates, and uses pp60c-src to mediate its mitogenicity. Blood 2004; 103: 1464–1471.

    Article  CAS  PubMed  Google Scholar 

  47. Fujimoto J, Shiota M, Iwahara T, Seki N, Satoh H, Mori S et al. Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5). Proc Natl Acad Sci USA 1996; 93: 4181–4186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Villalva C, Trempat P, Greenland C, Thomas C, Girard JP, Moebius F et al. Isolation of differentially expressed genes in NPM-ALK-positive anaplastic large cell lymphoma. Br J Haematol 2002; 118: 791–798.

    Article  CAS  PubMed  Google Scholar 

  49. Ouyang T, Bai RY, Bassermann F, von Klitzing C, Klumpen S, Miething C et al. Identification and characterization of a nuclear interacting partner of anaplastic lymphoma kinase (NIPA). J Biol Chem 2003; 278: 30028–30036.

    Article  CAS  PubMed  Google Scholar 

  50. Pronk GJ, de Vries-Smits AM, Buday L, Downward J, Maassen JA, Medema RH et al. Involvement of Shc in insulin- and epidermal growth factor-induced activation of p21ras. Mol Cell Biol 1994; 14: 1575–1581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Englund C, Loren CE, Grabbe C, Varshney GK, Deleuil F, Hallberg B et al. Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion. Nature 2003; 425: 512–516.

    Article  CAS  PubMed  Google Scholar 

  52. Lee HH, Norris A, Weiss JB, Frasch M . Jelly belly protein activates the receptor tyrosine kinase Alk to specify visceral muscle pioneers. Nature 2003; 425: 507–512.

    Article  CAS  PubMed  Google Scholar 

  53. Cook SJ, Aziz N, McMahon M . The repertoire of fos and jun proteins expressed during the G1 phase of the cell cycle is determined by the duration of mitogen-activated protein kinase activation. Mol Cell Biol 1999; 19: 330–341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kennedy NJ, Davis RJ . Role of JNK in tumor development. Cell Cycle 2003; 2: 199–201.

    CAS  PubMed  Google Scholar 

  55. Eferl R, Wagner EF . AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 2003; 3: 859–868.

    Article  CAS  PubMed  Google Scholar 

  56. Amin HM, McDonnell TJ, Ma Y, Lin Q, Fujio Y, Kunisada K et al. Inhibition of JAK3 induces apoptosis and decreases anaplastic lymphoma kinase activity in anaplastic large cell lymphoma. Oncogene 2004; 23: 5426–5434.

    Article  CAS  PubMed  Google Scholar 

  57. Amin HM, Medeiros LJ, Ma Y, Feretzaki M, Das P, Leventaki V et al. Selective inhibition of STAT3 induces apoptosis and G(1) cell cycle arrest in ALK-positive anaplastic large cell lymphoma. Oncogene 2003; 22: 5399–5407.

    Article  CAS  PubMed  Google Scholar 

  58. Khoury JD, Medeiros LJ, Rassidakis GZ, Yared MA, Tsioli P, Leventaki V et al. Differential expression and clinical significance of tyrosine-phosphorylated STAT3 in ALK+ and ALK− anaplastic large cell lymphoma. Clin Cancer Res 2003; 9: 3692–3699.

    CAS  PubMed  Google Scholar 

  59. Lai R, Rassidakis GZ, Medeiros LJ, Ramdas L, Goy AH, Cutler C et al. Signal transducer and activator of transcription-3 activation contributes to high tissue inhibitor of metalloproteinase-1 expression in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Am J Pathol 2004; 164: 2251–2258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Slupianek A, Hoser G, Majsterek I, Bronisz A, Malecki M, Blasiak J et al. Fusion tyrosine kinases induce drug resistance by stimulation of homology-dependent recombination repair, prolongation of G(2)/M phase, and protection from apoptosis. Mol Cell Biol 2002; 22: 4189–4201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME . Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997; 91: 231–241.

    Article  CAS  PubMed  Google Scholar 

  62. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999; 96: 857–868.

    Article  CAS  PubMed  Google Scholar 

  63. Gu TL, Tothova Z, Scheijen B, Griffin JD, Gilliland DG, Sternberg DW . NPM-ALK fusion kinase of anaplastic large-cell lymphoma regulates survival and proliferative signaling through modulation of FOXO3a. Blood 2004; 103: 4622–4629.

    Article  CAS  PubMed  Google Scholar 

  64. Slupianek A, Skorski T . NPM/ALK downregulates p27Kip1 in a PI-3K-dependent manner. Exp Hematol 2004; 32: 1265–1271.

    Article  CAS  PubMed  Google Scholar 

  65. Rassidakis GZ, Feretzaki M, Atwell C, Grammatikakis I, Lin Q, Lai R et al. Inhibition of Akt increases p27Kip1 levels and induces cell cycle arrest in anaplastic large cell lymphoma. Blood 2005; 105: 827–829.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

SDT is supported with funding from the Leukaemia Research Fund (UK) and the Leukemia and Lymphoma Society (USA) (6018-03). DRA is supported with funding from the Biotechnology and Biological Sciences Research Council.

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  1. Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge, CB2 4AT, UK

    S D Turner & D R Alexander

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Turner, S., Alexander, D. What have we learnt from mouse models of NPM-ALK-induced lymphomagenesis?. Leukemia 19, 1128–1134 (2005). https://doi.org/10.1038/sj.leu.2403797

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