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

作者：Isoda Takeshi; Takagi Masatoshi^*; Piao Jinhua; Nakagama Shun; Sato Masaki; Masuda Kyoko; Ikawa Tomokatsu; Azuma Miyuki; Morio Tomohiro; Kawamoto Hiroshi; Mizutani Shuki

来源：Blood, 2012, 120(4): 789-799.

DOI：10.1182/blood-2012-02-413195

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-delta 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 beta- or gamma delta-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-alpha/delta locus breaks occur and are left unrepaired during the troublesome beta- or gamma delta-selection checkpoints. By getting through these selection checkpoints, some of the clones with random or nonrandom chromosomal translocations involving TCR-alpha/delta 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. (Blood. 2012;120(4):789-799)

• 出版日期2012-7-26