Abnormal rearrangement within the a/d T-cell receptor locus in lymphomas from Atm-deficient mice

Atm-deficient mice (Atm2/2) recapitulate many aspects of the ataxia telangiectasia (AT) syndrome, including the susceptibility to tumors of lymphoid origin. To investigate the mechanism of tumorigenesis, we have examined a panel of 8 thymic lymphomas from Atm2/2 mice. All Atm2/2 tumors are of thymic lymphoblastoid origin, display an immature CD32 and CD41/ CD81 phenotype, and arise coincident with V(D)J recombination. Cytogenetically, all tumors are diploid or near diploid but exhibit multiple chromosome aberrations with an average of 4 abnormal chromosomes per tumor. All the tumors revealed chromosome 14 rearrangements precisely at the T-cell receptora/d (Tcra/d) locus, suggesting the involvement of V(D)J recombination in these translocations. In addition, 11.5% of Atm2/2 peripheral T cells showed chromosome 14 translocations, suggesting that rearrangements at the Tcra/d locus occur early during tumor development in the absence of ATM. However, additional genetic aberrations are required for tumorigenesis. For example, translocations involving chromosome 12, often with chromosome 14 (more than 60%), and partial or complete trisomy of chromosome 15, with copy number increases of the c-myc oncogene were frequently observed. These observations suggest that ATM is required for normal rearrangement of the Tcra/d locus but not for V(D)J recombination at other loci. The mechanisms that lead to tumorigenesis may be due to the involvement of ATM in monitoring doublestranded DNA breaks. (Blood. 2000;96: 1940-1946)