Regulatory Elements in the Immunoglobulin Heavy Chain Gene 3′-Enhancers Induce c-myc Deregulation and Lymphomagenesis in Murine B Cells
| Autor: | Linda M. Boxer, Jinghong Wang |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Time Factors
Lymphoma Apoptosis Biochemistry Mice immune system diseases hemic and lymphatic diseases Genes Regulator RNA Small Interfering Promoter Regions Genetic B-cell lymphoma Etoposide Gene Rearrangement B-Lymphocytes education.field_of_study biology Cell Cycle Nuclear Proteins Gene targeting Proto-Oncogene Proteins c-mdm2 Flow Cytometry Enhancer Elements Genetic medicine.anatomical_structure Proto-Oncogene Proteins c-bcl-2 Antibody Immunoglobulin Heavy Chains Signal Transduction Blotting Western Genetic Vectors Population bcl-X Protein Bone Marrow Cells Mice Transgenic Transfection Immunoglobulin light chain Proto-Oncogene Proteins c-myc Proto-Oncogene Proteins medicine Animals RNA Messenger education Molecular Biology Alleles B cell Cell Proliferation Dose-Response Relationship Drug Models Genetic Cell Biology medicine.disease Molecular biology biology.protein Immunoglobulin heavy chain Spleen |
| Zdroj: | Journal of Biological Chemistry. 280:12766-12773 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m412446200 |
| Popis: | Burkitt's lymphoma is invariably associated with chromosomal translocations that juxtapose the c-myc proto-oncogene with regulatory elements of the immunoglobulin heavy (IgH) or light chain loci resulting in the deregulation of c-myc expression. However, the enhancer elements mediating c-myc deregulation in vivo remain largely unidentified. To investigate the role of the IgH 3'-enhancers in c-myc 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 into the 5'-region of the c-myc locus. The IgH 3'-enhancers induced the up-regulation of c-myc expression specifically in B cells of IgH-3'-E-myc mice. After approximately 10 months, the mice developed a Burkitt-like B cell lymphoma with the phenotype of B220+, IgM+, and IgD(low). Analysis of immunoglobulin gene rearrangements indicated that the lymphoma cells were of clonal origin. The presence of a rapidly expanding population of B cells in the spleen and bone marrow of young knock-in mice at 2-4 months of age was observed. Premalignant splenic B cells of knock-in mice showed higher spontaneous and induced apoptosis; however, malignant B cells were more resistant to apoptosis. The p53-ARF-Mdm2 pathway was disabled in half of the lymphomas examined, in most cases through Mdm2 overexpression. Although c-myc expression was increased in premalignant B cells, the promoter shift from P2 to P1 was observed only in malignant B cells. Our studies demonstrate that the IgH 3'-enhancers play an important role in c-myc deregulation and B cell lymphomagenesis in vivo. |
| Databáze: | OpenAIRE |
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