Aberrant TCR delta rearrangement underlies the T-cell lymphocytopenia and t(12;14) translocation associated with ATM deficiency

作者：Jiang Wenxia; Lee Brian J; Li Chen; Dubois Richard L; Gostissa Monica; Alt Frederick W; Zha Shan^*

来源：Blood, 2015, 125(17): 2665-2668.

DOI：10.1182/blood-2015-01-622621

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.

• 出版日期2015-4-23