Chimeric IgH-TCR/ translocations in T lymphocytes mediated by RAG

Academic Article

Abstract

  • Translocations involving the T cell receptor alpha/delta (TCRα/δ) chain locus, which bring oncogenes in the proximity of the TCRα enhancer, are one of the hallmark features of human T cell malignancies from ataxia telangiectasia (AT) and non-AT patients. These lesions are frequently generated by the fusion of DNA breaks at the TCRα/δ locus to a disperse region centromeric of the immunoglobulin heavy chain (IgH) locus. Aberrant VDJ joining accounts for TCRα/δ associated DNA cleavage, but the molecular mechanism that leads to generation of the "oncogene partner" DNA break is unclear. Here we show that in ATM deficient primary mouse T cells, IgH/ TCRα/δ fusions arise at a remarkably similar frequency as in human AT lymphocytes. Recombinase-activating gene (RAG) is responsible for both TCRα/δ as well as IgH associated breaks on chromosome 12 (Chr12), which are subject to varying degrees of chromosomal degradation. We suggest a new model for how oncogenic translocations can arise from two non-concerted physiological DSBs. ©2009 Landes Bioscience.
  • Authors

    Published In

  • Cell Cycle  Journal
  • Digital Object Identifier (doi)

    Author List

  • Callén E; Bunting S; Huang CY; Difilippantonio MJ; Wong N; Khor B; Mahowald G; Kruhlak MJ; Ried T; Sleckman BP
  • Start Page

  • 2408
  • End Page

  • 2412
  • Volume

  • 8
  • Issue

  • 15