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Blood, 1 March 2007, Vol. 109, No. 5, pp. 1887-1896.
Prepublished online as a Blood First Edition Paper on October 31, 2006; DOI 10.1182/blood-2006-05-020917.
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Submitted May 3, 2006
Accepted October 19, 2006
ATM deficiency disrupts TCR locus integrity and the maturation of CD4+CD8+ thymocytes
Irina R Matei, Rebecca A Gladdy, Lauryl M.J Nutter, Angelo Canty, Cynthia J Guidos, and Jayne S Danska*
Program in Developmental Biology, Hospital for Sick Children Research Institute, Toronto, Canada
Department of Surgery, University of Toronto, Toronto, Canada
Department of Mathematics and Statistics, McMaster University, Ontario, Canada
Department of Immunology, University of Toronto, Toronto, Canada
Department of Medical Biophysics, University of Toronto, Toronto, Canada
* Corresponding author; email: jayne.danska{at}sickkids.ca.
Mutations in ATM (ataxia-telangiectasia mutated) cause Ataxia-Telangiectasia (AT), a disease characterized by neurodegeneration, sterility, immunodeficiency, and T cell leukemia. Defective ATM-mediated DNA damage responses underlie many aspects of the AT syndrome, but the basis for the immune deficiency has not been defined. ATM associates with DNA double-strand breaks (DSB), and some evidence suggests that ATM may regulate V(D)J recombination. However, it remains unclear how ATM loss compromises lymphocyte development in vivo. Here we show that TCR -dependent proliferation and production of TCRlow CD4+CD8+ (DP) thymocytes occurred normally in Atm-/- mice. In striking contrast, the post-mitotic maturation of TCRlow DP precursors into TCRint DP cells and TCRhi mature thymocytes was profoundly impaired. Furthermore, Atm-/- thymocytes expressed abnormally low amounts of TCR mRNA and protein. These defects were not attributable to the induction of a BCL-2 sensitive apoptotic pathway. Rather, they were associated with frequent bi-allelic loss of distal V gene segments in DP thymocytes, revealing that ATM maintains TCR locus integrity as it undergoes V(D)J recombination, Collectively, our data demonstrate that ATM loss increases the frequency of aberrant TCR deletion events, which compromise DP thymocyte maturation and likely promote the generation of oncogenic TCR translocations.
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