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Animal Models

The immunoglobulin heavy chain gene 3′ enhancers induce Bcl2 deregulation and lymphomagenesis in murine B cells

Leukemia volume 25, pages 1484–1493 (2011)Cite this article

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Abstract

Human follicular B-cell lymphoma is associated with the t(14;18) chromosomal translocation that juxtaposes the Bcl2 proto-oncogene with the immunoglobulin heavy chain (Igh) locus, resulting in the deregulated expression of Bcl2. Our previous studies have shown that the Igh 3′ enhancers deregulate the Bcl2 expression in vitro. However, the effects of the Igh 3′ enhancer elements on Bcl2 expression in vivo are not known. To investigate the role of the Igh 3′ enhancers in Bcl2 deregulation, we used gene targeting to generate knock-in mice in which four DNase I-hypersensitive regions from the murine Igh 3′ region were integrated 3′ of the Bcl2 locus. Increased levels of Bcl2 mRNA and protein were observed in the B cells of Igh-3′E-bcl2 mice. B cells from Igh-3′E-bcl2 mice showed an extended survival in vitro compared with B cells from wild-type (Wt) mice. The Bcl2 promoter shift from P1 (the 5′ promoter) to P2 (the 3′ promoter) was observed in B cells from Igh-3′E-bcl2 mice, similar to human t(14;18) lymphomas. The IgH-3′E-bcl2 mice developed monoclonal B-cell follicular lymphomas, which were slowly progressive. These studies show that the Igh 3′ enhancers have an important role in the deregulation of Bcl2 and B-cell lymphomagenesis in vivo.

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Acknowledgements

We thank Evelyn Resurreccion, Stanford University, for her help and expertize with sectioning and immunohistochemical staining. This work was supported by the National Institutes of Health Grant CA56764.

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Authors and Affiliations

  1. Center for Molecular Biology in Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

    H Xiang, E J Noonan, J Wang, H Duan, L Ma & L M Boxer

  2. Division of Hematology; Department of Medicine, Stanford University School of Medicine,

    H Xiang, E J Noonan, J Wang, H Duan, L Ma & L M Boxer

  3. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    H Xiang, E J Noonan, J Wang, H Duan, L Ma & L M Boxer

  4. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA

    S Michie

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Correspondence to L M Boxer.

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Xiang, H., Noonan, E., Wang, J. et al. The immunoglobulin heavy chain gene 3′ enhancers induce Bcl2 deregulation and lymphomagenesis in murine B cells. Leukemia 25, 1484–1493 (2011). https://doi.org/10.1038/leu.2011.115

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