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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.


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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 {alpha}{beta} 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.


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