| First Author | Jiang W | Year | 2015 |
| Journal | Blood | Volume | 125 |
| Issue | 17 | Pages | 2665-8 |
| PubMed ID | 25721125 | Mgi Jnum | J:222125 |
| Mgi Id | MGI:5643997 | Doi | 10.1182/blood-2015-01-622621 |
| Citation | Jiang W, et al. (2015) Aberrant TCRdelta rearrangement underlies the T-cell lymphocytopenia and t(12;14) translocation associated with ATM deficiency. Blood 125(17):2665-8 |
| abstractText | 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 (TCRalpha/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 TCRdelta enhancer (Edelta), which initiates TCRdelta rearrangement, significantly improves alphabeta 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 TCRdelta locus as the molecular origin of both lymphocytopenia and the signature t(12;14) translocations associated with ATM deficiency. |
