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  • Original Paper
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The oncogenic fusion protein nucleophosmin–anaplastic lymphoma kinase (NPM–ALK) induces two distinct malignant phenotypes in a murine retroviral transplantation model

Abstract

A t(2;5) (p23;q35) chromosomal translocation can be found in a high percentage of anaplastic large-cell lymphomas (ALCL). This genetic abnormality leads to the expression of the NPM–ALK fusion protein, which encodes a constitutively active tyrosine kinase that plays a causative role in lymphomagenesis. Employing a modified infection/transplantation protocol utilizing an MSCV-based vector, we were able to reproducibly induce two phenotypically different lymphoma-like diseases dependent on the retroviral titers used. The first phenotype presented as a polyclonal histiocytic malignancy of myeloid/macrophage origin with a short latency period of 3–4 weeks. Clinically, the diseased mice showed rapidly progressive wasting, lymphadenopathy and pancytopenia. Mice displaying the second phenotype developed monoclonal B-lymphoid tumors with a longer latency of approximately 12–16 weeks, primarily involving the spleen and the bone marrow, with less extensive lymph node but also histologically evident extranodal organ infiltration by large immature plasmoblastic cells. The described retroviral mouse model will be useful to analyse the role of NPM–ALK in lymphomagenesis in vivo and may contribute to the development of new treatment options for NPM–ALK induced malignancies.

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Acknowledgements

JD is supported by a grant from the Wilhelm-Sander Stiftung. CM is supported by a fellowship from the Deutsche Jose Carreras Leukämie Stiftung (DJCLS 2001/NAT-2). The work was also supported by National Cancer Institute (NCI) Grant CA69129 (SWM), NCI Cancer Center Core Grant CA21765 and by the American Lebanese Syrian Associated Charities (ALSAC), St Jude Children's Research Hospital. We thank W Pear for supplying the MigRI retroviral vector.

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Correspondence to Justus Duyster.

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Miething, C., Grundler, R., Fend, F. et al. The oncogenic fusion protein nucleophosmin–anaplastic lymphoma kinase (NPM–ALK) induces two distinct malignant phenotypes in a murine retroviral transplantation model. Oncogene 22, 4642–4647 (2003). https://doi.org/10.1038/sj.onc.1206575

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