Follicular lymphoma is characterized by the t(14;18) translocation, which links the bcl-2 gene with the immunoglobulin heavy chain gene (IgH). The translocated bcl-2 allele is expressed at high levels, and the normal allele is silent. The increased levels of Bcl-2 contribute to resistance to chemotherapeutic agents, and follicular lymphoma is rarely cured. We have investigated how the translocated bcl-2 gene is deregulated by the IgH locus and have identified regulatory sites in the bcl-2 promoter and in the 3'IgH enhancers. The involvement of these sites has been confirmed in an episomal model of the translocation. In this proposal, we will build upon our previous results using a murine model of deregulated bcl-2 expression induced by the IgH 3' enhancers (IgH-bcl-2 mice). Our studies have provided insight into the mechanisms involved in the deregulation of bcl-2 expression and have also provided evidence that the activation of bcl-2 expression is more complex than previously thought. Based on these results, we propose to more closely examine the regulation of the two bcl-2 promoters in normal B cells and study how one promoter influences the other. In addition, our data demonstrate that while the IgH enhancers are required for the deregulation of bcl-2 expression, they are not sufficient, and that additional changes occur during the transformation process of the B cell. Our investigations will be performed on the bcl-2 gene in the genomic context so that we can study the chromosomal structure at the bcl-2 promoter and define the interactions with the IgH enhancers. Additionally, we will characterize the lymphomas that develop in IgH-bcl-2 mice and compare them to human follicular lymphomas. Information that we gain from the studies on mechanisms involved in bcl-2 deregulation will be utilized to interfere with bcl-2 expression in the IgH-bcl-2 mice as a method to prevent or treat the lymphomas. 1. Characterization of the mechanisms involved in the lack of transcription from the bcl-2 P2 promoter in the absence of the IgH enhancers. 2. Characterization of the molecular mechanisms of bcl-2 deregulation in B cells from IgH-bcl-2 mice to further clarify the mechanisms of bcl-2 deregulation in t(14;18) lymphomas. 3. Development of a preclinical model for t(14;18) lymphomas utilizing the IgH-bcl-2 mice. Project Narrative We are studying a malignancy of B lymphocytes to understand the role of a genetic abnormality involving the bcl-2 gene, which codes for a protein that extends the survival of the malignant cells. Our investigations are designed to determine how the bcl-2 gene is expressed at high levels and to develop a mouse model for the human malignancy (follicular lymphoma). These studies will provide new information that can be used to treat the disease in humans.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Howcroft, Thomas K
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Palo Alto Institute for Research & Edu, Inc.
Palo Alto
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Xiang, H; Noonan, E J; Wang, J et al. (2011) The immunoglobulin heavy chain gene 3' enhancers induce Bcl2 deregulation and lymphomagenesis in murine B cells. Leukemia 25:1484-93
Duan, H; Heckman, C A; Boxer, L M (2007) The immunoglobulin heavy-chain gene 3'enhancers deregulate bcl-2 promoter usage in t(14;18) lymphoma cells. Oncogene 26:2635-41
Xiang, Hong; Wang, Jinghong; Boxer, Linda M (2006) Role of the cyclic AMP response element in the bcl-2 promoter in the regulation of endogenous Bcl-2 expression and apoptosis in murine B cells. Mol Cell Biol 26:8599-606
Heckman, Caroline A; Wheeler, Melissa A; Boxer, Linda M (2003) Regulation of Bcl-2 expression by C/EBP in t(14;18) lymphoma cells. Oncogene 22:7891-9
Heckman, Caroline A; Cao, Thai; Somsouk, Lina et al. (2003) Critical elements of the immunoglobulin heavy chain gene enhancers for deregulated expression of bcl-2. Cancer Res 63:6666-73
Zheng, Z; Venkatapathy, S; Rao, G et al. (2002) Expression profiling of B cell chronic lymphocytic leukemia suggests deficient CD1-mediated immunity, polarized cytokine response, altered adhesion and increased intracellular protein transport and processing of leukemic cells. Leukemia 16:2429-37
Heckman, Caroline A; Mehew, John W; Boxer, Linda M (2002) NF-kappaB activates Bcl-2 expression in t(14;18) lymphoma cells. Oncogene 21:3898-908
Arcinas, M; Heckman, C A; Mehew, J W et al. (2001) Molecular mechanisms of transcriptional control of bcl-2 and c-myc in follicular and transformed lymphoma. Cancer Res 61:5202-6
Wu , Y; Mehew, J W; Heckman, C A et al. (2001) Negative regulation of bcl-2 expression by p53 in hematopoietic cells. Oncogene 20:240-51
Heckman, C A; Mehew, J W; Ying, G G et al. (2000) A-Myb up-regulates Bcl-2 through a Cdx binding site in t(14;18) lymphoma cells. J Biol Chem 275:6499-508

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