Abnormal rearrangement within the alpha/delta T-cell receptor locus in lymphomas from Atm-deficient mice.
Atm-deficient mice (Atm(-/-)) 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 Atm(-/-) mice. All Atm(-/-) tumors are of thymic lymphoblastoid origin, display an immature CD3(-) and CD4(+)/CD8(+) 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 receptoralpha/delta (Tcralpha/delta) locus, suggesting the involvement of V(D)J recombination in these translocations. In addition, 11.5% of Atm(-/-) peripheral T cells showed chromosome 14 translocations, suggesting that rearrangements at the Tcralpha/delta 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 Tcralpha/delta 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 double-stranded DNA breaks. (Blood. 2000;96:1940-1946)
Liyanage
M
M
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Weaver
Z
Z
Barlow
C
C
Coleman
A
A
Pankratz
D G
DG
Anderson
S
S
Wynshaw-Boris
A
A
Ried
T
T
D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000378:metabolism; D002869:Chromosome Aberrations; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor / Q000235:genetics*; D016694:Gene Rearrangement, delta-Chain T-Cell Antigen Receptor / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D013953:Thymus Neoplasms / Q000235:genetics / Q000473:pathology
D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; C490393:Tcl1 protein, mouse