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

• Published in: Leukemia Vol. 25; no. 9; pp. 1484 - 1493
• Main Authors: Xiang, H, Noonan, E J, Wang, J, Duan, H, Ma, L, Michie, S, Boxer, L M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2011; Nature Publishing Group
• Subjects: 3' Untranslated Regions - genetics; 692/420/2489/68; 692/699/67/1990/291/1621/1915; Animals; B cells; B-cell lymphoma; B-Lymphocytes - pathology; Biological and medical sciences; Blotting, Southern; Blotting, Western; Cancer Research; Cell Cycle; Cell Differentiation; Cell Survival; Cells, Cultured; Chains; Chromosome aberrations; Chromosome translocations; Chromosomes; Cloning; Critical Care Medicine; Deoxyribonuclease; Deregulation; Enhancer Elements, Genetic - genetics; Enhancers; Female; Flow Cytometry; Fluorescent Antibody Technique; Gene expression; Gene targeting; Genes, Immunoglobulin Heavy Chain - genetics; Heavy chains; Hematologic and hematopoietic diseases; Hematology; Humans; Immunoglobulins; In vivo methods and tests; Intensive; Internal Medicine; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Loci; Lymphocytes B; Lymphoma; Lymphoma, B-Cell - etiology; Lymphoma, B-Cell - pathology; Male; Medical genetics; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; mRNA; Oncology; original-article; Physiological aspects; Polymerase Chain Reaction; Promoter Regions, Genetic - genetics; Proteins; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-bcl-2; Translocation; United States; Palo Alto California; United States > US; mouse models; BCL2; t(14;18); enhancer; lymphoma; Chromosomal aberration; Animal model; Carcinogenesis; Lymphoproliferative syndrome; Genetics; Protooncogene; Chromosome translocation; Heavy peptide chain; Immunoglobulins; Hematology; Rodentia; Malignant hemopathy; B-Lymphocyte; Lymphoid neoplasm; Igh enhancer; Lymphoma; Vertebrata; Mammalia; Abnormal chromosome E18; Mouse; Animal; C-Onc gene; Abnormal chromosome D14; Abnormal chromosome; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2011.115

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 .