Vav-promoter regulated oncogenic fusion protein npm-alk in transgenic mice causes b-cell lymphomas with hyperactive jun kinase

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

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Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS DELETION OF THE TRANSCRIPTIONAL REGULATOR TFAP4 ACCELERATES C-MYC-DRIVEN LYMPHOMAGENESIS Article Open access 09 March 2023

DISTINCT ONCOGENIC PHENOTYPES IN HEMATOPOIETIC SPECIFIC DELETIONS OF TRP53 Article Open access 09 May 2023 PRL3 ENHANCES T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA GROWTH THROUGH SUPPRESSING T-CELL

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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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Laboratory of Lymphocyte Signalling and Development,

Molecular Immunology Programme, The Babraham Institute, Babraham, Cambridge, CB2 4AT, UK Suzanne D Turner & Denis R Alexander * Cancer Medicine Unit, St James University Hospital, Leeds,

LS97TF, UK Reuben Tooze & Kenneth Maclennan Authors * Suzanne D Turner View author publications You can also search for this author inPubMed Google Scholar * Reuben Tooze View author

publications You can also search for this author inPubMed Google Scholar * Kenneth Maclennan View author publications You can also search for this author inPubMed Google Scholar * Denis R

Alexander View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Denis R Alexander. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 06 November 2002 * Revised: 30 July 2003 *

Accepted: 31 July 2003 * Published: 30 October 2003 * Issue Date: 30 October 2003 * DOI: https://doi.org/10.1038/sj.onc.1207048 SHARE THIS ARTICLE Anyone you share the following link with

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content-sharing initiative KEYWORDS * NPM-ALK * lymphoma * mouse model * Jun kinase