|
|
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.
Previous Article | Table of Contents | Next Article 
HEMATOPOIESIS
ATM deficiency disrupts Tcra locus integrity and the maturation of CD4+CD8+ thymocytes
Irina R. Matei1,2,
Rebecca A. Gladdy1,3,
Lauryl M. J. Nutter1,
Angelo Canty5,
Cynthia J. Guidos1,4, and
Jayne S. Danska1,2,4
1 Program in Developmental and Stem Cell Biology, The Hospital for Sick Children Research Institute, University of Toronto, ON, Canada;
2 Department of Medical Biophysics, University of Toronto, ON, Canada;
3 Department of Surgery, University of Toronto, ON, Canada;
4 Department of Immunology, University of Toronto, ON, Canada;
5 Department of Mathematics and Statistics, McMaster University, Hamilton, ON, Canada
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 (DSBs), 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 T-cell receptor ß (TCRß)dependent proliferation and production of TCRßlow CD4+CD8+ (DP) thymocytes occurred normally in Atm/ mice. In striking contrast, the postmitotic maturation of TCRßlow DP precursors into TCRßint DP cells and TCRßhi 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-2sensitive apoptotic pathway. Rather, they were associated with frequent biallelic loss of distal Va gene segments in DP thymocytes, revealing that ATM maintains Tcra locus integrity as it undergoes V(D)J recombination. Collectively, our data demonstrate that ATM loss increases the frequency of aberrant Tcra deletion events, which compromise DP thymocyte maturation and likely promote the generation of oncogenic TCR translocations.

CiteULike Connotea Del.icio.us Digg Reddit Technorati What's this?
This article has been cited by other articles:

|
 |

|
 |
 
B. Yin, V. Savic, M. M. Juntilla, A. L. Bredemeyer, K. S. Yang-Iott, B. A. Helmink, G. A. Koretzky, B. P. Sleckman, and C. H. Bassing
Histone H2AX stabilizes broken DNA strands to suppress chromosome breaks and translocations during V(D)J recombination
J. Exp. Med.,
November 23, 2009;
206(12):
2625 - 2639.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. Ren, X. Li, and J. K. Cowell
Genetic fingerprinting of the development and progression of T-cell lymphoma in a murine model of atypical myeloproliferative disorder initiated by the ZNF198-fibroblast growth factor receptor-1 chimeric tyrosine kinase
Blood,
August 20, 2009;
114(8):
1576 - 1584.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
B. A. Helmink, A. L. Bredemeyer, B.-S. Lee, C.-Y. Huang, G. G. Sharma, L. M. Walker, J. J. Bednarski, W.-L. Lee, T. K. Pandita, C. H. Bassing, et al.
MRN complex function in the repair of chromosomal Rag-mediated DNA double-strand breaks
J. Exp. Med.,
March 16, 2009;
206(3):
669 - 679.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. F. Lavin, N. Gueven, S. Bottle, and R. A. Gatti
Current and potential therapeutic strategies for the treatment of ataxia-telangiectasia
Br. Med. Bull.,
June 23, 2007;
(2007)
ldm012v1.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. S. Vacchio, A. Olaru, F. Livak, and R. J. Hodes
ATM deficiency impairs thymocyte maturation because of defective resolution of T cell receptor {alpha} locus coding end breaks
PNAS,
April 10, 2007;
104(15):
6323 - 6328.
[Abstract]
[Full Text]
[PDF]
|
 |
|
|
|