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Expression of constitutively nuclear cyclin D1 in murine lymphocytes induces B-cell lymphoma

Oncogene volume 25, pages 998–1007 (2006)Cite this article

Abstract

Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by overexpression of cyclin D1 due to the t(11;14) chromosomal translocation. While expression of cyclin D1 correlates with MCL development, expression of wild-type (WT) cyclin D1 transgene in murine lymphocytes is unable to drive B-cell lymphoma. As cyclin D1 mutants that are refractory to nuclear export display heighten oncogenicity in vitro compared with WT D1, we generated mice expressing FLAG-D1/T286A, a constitutively nuclear mutant, under the control of the immunoglobulin enhancer, Eμ. D1/T286A transgenic mice universally develop a mature B-cell lymphoma. Expression of D1/T286A in B lymphocytes results in S?phase entry in resting lymphocytes and increased apoptosis in spleens of young premalignant mice. Lymphoma onset correlates with perturbations in p53/MDM2/p19Arf expression and with BcL-2 overexpression suggesting that alterations in one or both of these pathways may contribute to lymphoma development. Our results describe a cyclin D1-driven model of B-cell lymphomagenesis and provide evidence that nuclear-retention of cyclin D1 is oncogenic in vivo.

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Acknowledgements

We would like to thank Anton Berns (The Netherlands Cancer Institute) and John Cleveland (St Jude Children's Research Hospital) for providing the TDK-TG90 construct. Martine F Roussel and Charles J Sherr (SJRH) for providing reagents and helpful suggestions. The transgenic and histology core at the Abramson Family Cancer Research Institute, University of Pennsylvania for technical assistance and Michal Marzec and Fengmin Lu, University of Pennsylvania for helpful suggestions. This work was supported by a Grant from the National Institutes of Health (NIH) CA93237(JAD) and CA89194 (MAW).

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  1. A B Gladden

    Present address: MGH Cancer Center, Harvard Medical School Department of Pathology, 149 13th Street, Charlestown, MA, 02129, USA

Authors and Affiliations

  1. Department of Cancer Biology, The Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    A B Gladden, R Woolery, P Aggarwal & J A Diehl

  2. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    M A Wasik

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  1. A B Gladden
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  2. R Woolery
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Correspondence to J A Diehl.

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Gladden, A., Woolery, R., Aggarwal, P. et al. Expression of constitutively nuclear cyclin D1 in murine lymphocytes induces B-cell lymphoma. Oncogene 25, 998–1007 (2006). https://doi.org/10.1038/sj.onc.1209147

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