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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 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 Citation Map 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 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 Immunobiology Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Aberrant V(D)J recombination is not required for rapid development of H2ax/p53-deficient thymic lymphomas with clonal translocations Craig H. Bassing1,2, Sheila Ranganath1, Mike Murphy1, Velibor Savic2, Meagan Gleason1, and Frederick W. Alt1 1 Howard Hughes Medical Institute, The Children's Hospital, Center for Blood Research (CBR), Institute for Biomedical Research, and Department of Genetics, Harvard University Medical School, Boston, MA; and 2 Cell and Molecular Biology Graduate Group, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, and the Abramson Family Cancer Research Institute, Philadelphia, PA Histone H2AX is required to maintain genomic stability in cells and to suppress malignant transformation of lymphocytes in mice. H2ax–/–p53–/– mice succumb predominantly to immature β 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. Because 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 do 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]

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