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

Blood. 2015 Apr 23;125(17):2665-8. doi: 10.1182/blood-2015-01-622621. Epub 2015 Feb 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Ataxia Telangiectasia / complications
  • Ataxia Telangiectasia / genetics
  • Ataxia Telangiectasia / pathology
  • Ataxia Telangiectasia Mutated Proteins / analysis
  • Ataxia Telangiectasia Mutated Proteins / genetics*
  • Chromosomes, Human, Pair 14 / genetics*
  • Gene Deletion
  • Genomic Instability
  • Humans
  • Lymphoma, T-Cell / complications
  • Lymphoma, T-Cell / genetics*
  • Lymphoma, T-Cell / pathology
  • Lymphopenia / complications
  • Lymphopenia / genetics*
  • Lymphopenia / pathology
  • Mice
  • Molecular Sequence Data
  • Receptors, Antigen, T-Cell, gamma-delta / genetics*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology*
  • Translocation, Genetic*
  • V(D)J Recombination


  • Receptors, Antigen, T-Cell, gamma-delta
  • Ataxia Telangiectasia Mutated Proteins

Supplementary concepts

  • T-Lymphocytopenia