Abstract
Ataxia telangiectasia mutated (ATM) deficiency predisposes humans and mice to T lineage lymphomas with recurrent chromosome 14 translocations involving the T cell receptor alpha/delta (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 (Ealpha) 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 Ealpha. Overall, our studies reveal previously unexpected mechanisms that contribute to the oncogenic transformation of ATM-deficient T lineage cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ataxia Telangiectasia Mutated Proteins
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Base Sequence
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Chromosomes, Mammalian / genetics
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Clone Cells
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Cytogenetic Analysis
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DNA-Binding Proteins / deficiency*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Enhancer Elements, Genetic / genetics
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Gene Amplification / genetics*
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Gene Rearrangement, delta-Chain T-Cell Antigen Receptor / genetics*
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Genetic Loci / genetics
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Lymphoma / enzymology*
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Lymphoma / genetics
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Lymphoma / pathology
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Mice
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Molecular Sequence Data
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Protein Serine-Threonine Kinases / deficiency*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Receptors, Antigen, T-Cell, gamma-delta / genetics*
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Thymus Neoplasms / enzymology*
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Thymus Neoplasms / genetics*
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Thymus Neoplasms / pathology
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Translocation, Genetic
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Tumor Suppressor Proteins / deficiency*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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Receptors, Antigen, T-Cell, gamma-delta
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Tumor Suppressor Proteins
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases