ATM-deficient thymic lymphoma is associated with aberrant tcrd rearrangement and gene amplification

Autor: Frederick W. Alt, James W. Brush, Craig H. Bassing, Richard A. Gatti, Harin Patel, A. Thomas Look, Michael M. Murphy, Shan Zha, Peter H. Goff, Takaomi Sanda, Suprawee Tepsuporn
Jazyk: angličtina
Rok vydání: 2010
Předmět:
Lymphoma
T cell
Immunology
Gene Rearrangement
delta-Chain T-Cell Antigen Receptor
Molecular Sequence Data
Chromosomal translocation
Locus (genetics)
Cell Cycle Proteins
Ataxia Telangiectasia Mutated Proteins
Biology
Protein Serine-Threonine Kinases
Article
Translocation
Genetic
03 medical and health sciences
Mice
0302 clinical medicine
Gene duplication
medicine
Immunology and Allergy
Animals
Chromosome 12
030304 developmental biology
Genetics
0303 health sciences
Base Sequence
Tumor Suppressor Proteins
Gene Amplification
Chromosome
Receptors
Antigen
T-Cell
gamma-delta
Gene rearrangement
Thymus Neoplasms
Molecular biology
Chromosomes
Mammalian
3. Good health
Clone Cells
DNA-Binding Proteins
medicine.anatomical_structure
Enhancer Elements
Genetic
Genetic Loci
Cytogenetic Analysis
030215 immunology
Zdroj: The Journal of Experimental Medicine
ISSN: 1540-9538
0022-1007
Popis: Ataxia telangiectasia mutated (ATM) deficiency predisposes humans and mice to T lineage lymphomas with recurrent chromosome 14 translocations involving the T cell receptor α/δ (Tcra/d) locus. Such translocations have been thought to result from aberrant repair of DNA double-strand breaks (DSBs) during Tcra locus V(D)J recombination, and to require the Tcra enhancer (Eα) for Tcra rearrangement or expression of the translocated oncogene. We now show that, in addition to the known chromosome 14 translocation, ATM-deficient mouse thymic lymphomas routinely contain a centromeric fragment of chromosome 14 that spans up to the 5′ boundary of the Tcra/d locus, at which position a 500-kb or larger region centromeric to Tcra/d is routinely amplified. In addition, they routinely contain a large deletion of the telomeric end of one copy of chromosome 12. In contrast to prior expectations, the recurrent translocations and amplifications involve V(D)J recombination–initiated breaks in the Tcrd locus, as opposed to the Tcra locus, and arise independently of the Eα. Overall, our studies reveal previously unexpected mechanisms that contribute to the oncogenic transformation of ATM-deficient T lineage cells.
Databáze: OpenAIRE
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