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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2163-2169. Prepublished online as a Blood First Edition Paper on September 13, 2007; DOI 10.1182/blood-2007-08-104760. This Article Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-08-104760v1 111/4/2163    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bassing, C. H. Articles by Alt, F. W. Search for Related Content PubMed PubMed Citation Articles by Bassing, C. H. Articles by Alt, F. W. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 1, 2007 Accepted August 30, 2007 Aberrant V(D)J recombination is not required for rapid development of H2ax/p53 deficient thymic lymphomas with clonal translocations Craig H. Bassing, Sheila Ranganath, Mike Murphy, Velibor Savic, Meagan Gleason, and Frederick W. Alt* Dept. of Pathology & Laboratory Medicine, Children's Hospital of Philadelphia, Univ. of Pennsylvania, & Abramson Family Cancer Research Inst., Philadelphia, PA, United States HHMI, Department of Genetics, The Children's Hospital, CBR Inst. for Biomedical Research, Harvard Medical School, Boston, MA, United States Cell & Molecular Biology Graduate Group, Children's Hospital of Philadelphia, Univ. of Pennsylvania, & Abramson Family Cancer Research Inst., Philadelphia, PA, United States * Corresponding author; email: alt{at}enders.tch.harvard.edu. Histone H2AX is required to maintain genomic stability in cells and suppress malignant transformation of lymphocytes in mice. H2ax-/-p53-/- mice succumb predominantly to immature T cell lymphomas with translocations, deletions, and genomic amplifications that do not involve T cell receptor (TCR). In addition, H2ax-/-p53-/- mice also develop at lower frequencies B and T lymphomas with antigen receptor locus translocations. V(D)J recombination is initiated through the programmed induction of DNA double strand breaks (DSBs) by the RAG1/RAG2 endonuclease. Since promiscuous RAG1/RAG2 cutting outside of antigen receptor loci can promote genomic instability, H2ax-/-p53-/- T lineage lymphomas might arise, at least in part, through erroneous V(D)J recombination. Here, we show that H2ax-/-p53-/-Rag2-/- mice exhibit a similar genetic predisposition as H2ax-/-p53-/- mice to thymic lymphoma with translocations, deletions, and amplifications. We also found that H2ax-/-p53+/-Rag2-/- mice often develop thymic lymphomas with loss or deletion of the p53+ locus. Our data show that aberrant V(D)J recombination is not required for rapid onset of H2ax/p53-deficient thymic lymphomas with genomic instability and that H2ax deficiency predisposes p53-/-Rag2-/- thymocytes to transformation associated with p53 inactivation. Thus, H2AX is essential for suppressing the transformation of developing thymocytes arising from the aberrant repair of spontaneous DSBs. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: RAGs found "not guilty": cleared by DNA evidence Albert G. Tsai and Michael R. Lieber Blood 2008 111: 1750. [Full Text] [PDF] 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]

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