Process for immune defect and chromosomal translocation during early thymocyte development lacking ATM.
Blood
; 120(4): 789-99, 2012 Jul 26.
Article
en En
| MEDLINE
| ID: mdl-22709691
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 ß- 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 ß- 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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Translocación Genética
/
Reordenamiento Génico de Linfocito T
/
Proteínas Serina-Treonina Quinasas
/
Proteínas de Ciclo Celular
/
Proteínas Supresoras de Tumor
/
Proteínas de Unión al ADN
/
Timocitos
/
Recombinación V(D)J
Límite:
Animals
Idioma:
En
Revista:
Blood
Año:
2012
Tipo del documento:
Article
País de afiliación:
Japón