期刊
BLOOD
卷 125, 期 17, 页码 2665-2668出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-01-622621
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资金
- National Institutes of Health (NIH) National Cancer Institute [5R01CA158073, 1R01CA184187, 1P01CA174653-01]
- American Cancer Society [RSG-13-038-01 DMC]
- NIH National Cancer Institute [P01CA109901, T32-CA09503]
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 alpha/delta (TCR alpha/delta) 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 TCR delta enhancer (E delta), which initiates TCR delta rearrangement, significantly improves alpha beta 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 TCRd locus as the molecular origin of both lymphocytopenia and the signature t(12;14) translocations associated with ATM deficiency.
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