Process for immune defect and chromosomal translocation during early thymocyte development lacking ATM

Blood. 2012 Jul 26;120(4):789-99. doi: 10.1182/blood-2012-02-413195. Epub 2012 Jun 18.

Abstract

Immune defect in ataxia telangiectasia patients has been attributed to either the failure of V(D)J recombination or class-switch recombination, and the chromosomal translocation in their lymphoma often involves the TCR gene. The ATM-deficient mouse exhibits fewer CD4 and CD8 single-positive T cells because of a failure to develop from the CD4(+)CD8(+) double-positive phase to the single-positive phase. Although the occurrence of chromosome 14 translocations involving TCR-δ gene in ATM-deficient lymphomas suggests that these are early events in T-cell development, a thorough analysis focusing on early T-cell development has never been performed. Here we demonstrate that ATM-deficient mouse thymocytes are perturbed in passing through the β- or γδ-selection checkpoint, leading in part to the developmental failure of T cells. Detailed karyotype analysis using the in vitro thymocyte development system revealed that RAG-mediated TCR-α/δ locus breaks occur and are left unrepaired during the troublesome β- or γδ-selection checkpoints. By getting through these selection checkpoints, some of the clones with random or nonrandom chromosomal translocations involving TCR-α/δ locus are selected and accumulate. Thus, our study visualized the first step of multistep evolutions toward lymphomagenesis in ATM-deficient thymocytes associated with T-lymphopenia and immunodeficiency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Ataxia Telangiectasia Mutated Proteins
  • Blotting, Western
  • Bone Marrow Transplantation
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Cycle
  • Cell Cycle Proteins / physiology*
  • Cell Differentiation
  • Cell Proliferation
  • DNA-Binding Proteins / physiology*
  • Female
  • Flow Cytometry
  • Gene Rearrangement, T-Lymphocyte*
  • Genomic Instability
  • In Situ Hybridization, Fluorescence
  • Karyotyping
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Serine-Threonine Kinases / physiology*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thymocytes / immunology*
  • Thymocytes / metabolism
  • Thymocytes / pathology*
  • Translocation, Genetic*
  • Tumor Suppressor Proteins / physiology*
  • V(D)J Recombination*

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • RNA, Messenger
  • Rag2 protein, mouse
  • Receptors, Antigen, T-Cell, alpha-beta
  • Tumor Suppressor Proteins
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein Serine-Threonine Kinases