Chimeric IgH-TCRα/δ translocations in T lymphocytes mediated by RAG
| Autor: | Bernard Khor, Samuel F. Bunting, Thomas Ried, Michael J. Difilippantonio, Grace K. Mahowald, Nancy Wong, Michael J. Kruhlak, Ching-Yu Huang, André Nussenzweig, Barry P. Sleckman, Elsa Callen |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Receptors
Antigen T-Cell alpha-beta T-Lymphocytes T cell Cell Cycle Proteins Locus (genetics) Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases Biology Translocation Genetic Mice Report medicine Animals Enhancer Molecular Biology Gene Mice Knockout Recombination Genetic Tumor Suppressor Proteins V(D)J recombination T-cell receptor Receptors Antigen T-Cell gamma-delta Cell Biology medicine.disease Molecular biology DNA-Binding Proteins medicine.anatomical_structure Ataxia-telangiectasia Immunoglobulin heavy chain Immunoglobulin Heavy Chains Developmental Biology |
| Popis: | Translocations involving the T cell receptor alpha/delta (TCRalpha/delta) chain locus, which bring oncogenes in the proximity of the TCRalpha enhancer, are one of the hallmark features of human T cell malignancies from ataxia telangiectasia (AT) and non-AT patients. These lesions are frequently generated by the fusion of DNA breaks at the TCRalpha/delta locus to a disperse region centromeric of the immunoglobulin heavy chain (IgH) locus. Aberrant VDJ joining accounts for TCRalpha/delta associated DNA cleavage, but the molecular mechanism that leads to generation of the "oncogene partner" DNA break is unclear. Here we show that in ATM deficient primary mouse T cells, IgH/TCRalpha/delta fusions arise at a remarkably similar frequency as in human AT lymphocytes. Recombinase-activating gene (RAG) is responsible for both TCRalpha/delta as well as IgH associated breaks on chromosome 12 (Chr12), which are subject to varying degrees of chromosomal degradation. We suggest a new model for how oncogenic translocations can arise from two non-concerted physiological DSBs. |
| Databáze: | OpenAIRE |
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