title: Aberrant TCRδ rearrangement underlies the T-cell lymphocytopenia and t(12;14) translocation associated with ATM deficiency.
abstract: Ataxia telangiectasia mutated (ATM) is a protein kinase and a master regulator of DNA-damage responses. Germline ATM inactivation causes ataxia-telangiectasia (A-T) syndrome with severe lymphocytopenia and greatly increased risk for T-cell lymphomas/leukemia. Both A-T and T-cell prolymphoblastic leukemia patients with somatic mutations of ATM frequently carry inv(14;14) between the T-cell receptor α/δ (TCRα/δ) and immunoglobulin H loci, but the molecular origin of this translocation remains elusive. ATM(-/-) mice recapitulate lymphocytopenia of A-T patients and routinely succumb to thymic lymphomas with t(12;14) translocation, syntenic to inv(14;14) in humans. Here we report that deletion of the TCRδ enhancer (Eδ), which initiates TCRδ rearrangement, significantly improves αβ T cell output and effectively prevents t(12;14) translocations in ATM(-/-) mice. These findings identify the genomic instability associated with V(D)J recombination at the TCRδ locus as the molecular origin of both lymphocytopenia and the signature t(12;14) translocations associated with ATM deficiency.
authors.affiliation: Department of Pathology and Cell Biology, Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Research Center, Columbia University Medical Center, New York, NY;
authors.forename: Wenxia
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Pathology and Cell Biology, Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Research Center, Columbia University Medical Center, New York, NY;
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lee
authors.affiliation: Department of Pathology and Cell Biology, Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Research Center, Columbia University Medical Center, New York, NY;
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Pathology and Cell Biology, Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Research Center, Columbia University Medical Center, New York, NY;
authors.forename: Richard L
authors.initials: RL
authors.lastname: Dubois
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA; and.
authors.forename: Monica
authors.initials: M
authors.lastname: Gostissa
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA; and.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.affiliation: Department of Pathology and Cell Biology, Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Research Center, Columbia University Medical Center, New York, NY; Division of Hematology, Oncology, and Stem Cell Transplantation, Department of Pediatrics, College for Physicians and Surgeons, Columbia University Medical Center, New York, NY.
authors.forename: Shan
authors.initials: S
authors.lastname: Zha
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001260:Ataxia Telangiectasia / Q000150:complications / Q000235:genetics / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000032:analysis / Q000235:genetics*; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D017353:Gene Deletion; D042822:Genomic Instability; D006801:Humans; D016399:Lymphoma, T-Cell / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008231:Lymphopenia / Q000150:complications / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D014178:Translocation, Genetic; D060152:V(D)J Recombination
chemical_list: D016692:Receptors, Antigen, T-Cell, gamma-delta; D064007:Ataxia Telangiectasia Mutated Proteins