Process for immune defect and chromosomal translocation during early thymocyte development lacking ATM.
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.
Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Takeshi
T
Isoda
Masatoshi
M
Takagi
Jinhua
J
Piao
Shun
S
Nakagama
Masaki
M
Sato
Kyoko
K
Masuda
Tomokatsu
T
Ikawa
Miyuki
M
Azuma
Tomohiro
T
Morio
Hiroshi
H
Kawamoto
Shuki
S
Mizutani
D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000502:physiology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D015329:Gene Rearrangement, T-Lymphocyte; D042822:Genomic Instability; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060168:Thymocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D060152:V(D)J Recombination
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C499308:Rag2 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases