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The immunoglobulin heavy-chain gene 3′ enhancers deregulate bcl-2 promoter usage in t(14;18) lymphoma cells

Oncogene volume 26, pages 2635–2641 (2007)Cite this article

Abstract

In t(14;18) lymphomas, bcl-2 is juxtaposed to the immunoglobulin heavy-chain gene (IgH), resulting in increased bcl-2 transcription and resistance to apoptosis. Regulatory elements of both the bcl-2 promoter and the IgH enhancers are believed to play a role in the increased expression of bcl-2 in t(14;18) lymphoma cells. In addition, transcription of the translocated bcl-2 allele is deregulated with activation of the normally minor bcl-2 P2 promoter. The mechanisms involved in the promoter shift from P1 to P2 are not known. We found that the murine IgH 3′ enhancers increased bcl-2 P2 promoter activity in an episomal model of the translocation, and IgH enhancer region HS12 had the greatest effect. Quantitative chromatin immunoprecipitation (ChIP) assays revealed that localized histone H3 hyperacetylation of the P2 promoter was observed on the translocated allele in t(14;18) DHL-4 cells and also on the stably transfected bcl-2 promoter-IgH enhancer episomal construct. Analysis of the HS12 enhancer region revealed that a previously identified nuclear factor-κB (NF-κB) site and a previously uncharacterized downstream Cdx site, both of which are conserved in the human and murine IgH enhancers, were important for its enhancer activity and promoter activation. ChIP assays showed that C/EBPβ bound to the HS12 Cdx site in vivo, and mutation of this site abrogated the binding of C/EBPβ. Reduced expression of C/EBPβ by transfection of small interfering RNA or interference with NF-κB activity decreased transcription from the bcl-2 promoters. These results demonstrate that the IgH 3′ enhancers, particularly HS12, are important for the deregulation of bcl-2 promoter usage in t(14;18) lymphomas.

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Acknowledgements

This work was supported by the National Institutes of Health Grant CA56764.

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  1. Veterans Affairs Palo Alto Health Care System and the Department of Medicine, Center for Molecular Biology in Medicine, Stanford University School of Medicine, Stanford, CA, USA

    H Duan, C A Heckman & L M Boxer

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  1. H Duan
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  2. C A Heckman
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Correspondence to L M Boxer.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Duan, H., Heckman, C. & Boxer, L. The immunoglobulin heavy-chain gene 3′ enhancers deregulate bcl-2 promoter usage in t(14;18) lymphoma cells. Oncogene 26, 2635–2641 (2007). https://doi.org/10.1038/sj.onc.1210061

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