The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20082271
The Journal of Experimental Medicine, Vol. 205, No. 13, 3079-3090
The Rockefeller University Press, 0022-1007 $30.00
© Wang et al.
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ARTICLE

 Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching

Jing H. Wang1,2,3,4, Frederick W. Alt1,2,3,4, Monica Gostissa1,2,3,4, Abhishek Datta1,2,3,4, Michael Murphy1,2,3,4, Marat B. Alimzhanov3, Kristen M. Coakley1,2,3,4, Klaus Rajewsky3,5, John P. Manis2,5, and Catherine T. Yan1,2,3,4

1 Howard Hughes Medical Institute, 2 The Children's Hospital, 3 Immune Disease Institute, 4 Department of Genetics, 5 Department of Pathology, Harvard Medical School, MA 02115

CORRESPONDENCE Frederick W. Alt: alt{at}enders.tch.harvard.edu

Nonhomologous end-joining (NHEJ) repairs DNA double-strand breaks (DSBs) during V(D)J recombination in developing lymphocytes and during immunoglobulin (Ig) heavy chain (IgH) class switch recombination (CSR) in peripheral B lymphocytes. We now show that CD21-cre–mediated deletion of the Xrcc4 NHEJ gene in p53-deficient peripheral B cells leads to recurrent surface Ig-negative B lymphomas ("CXP lymphomas"). Remarkably, CXP lymphomas arise from peripheral B cells that had attempted both receptor editing (secondary V[D]J recombination of Ig{kappa} and Ig{lambda} light chain genes) and IgH CSR subsequent to Xrcc4 deletion. Correspondingly, CXP tumors frequently harbored a CSR-based reciprocal chromosomal translocation that fused IgH to c-myc, as well as large chromosomal deletions or translocations involving Ig{kappa} or Ig{lambda}, with the latter fusing Ig{lambda} to oncogenes or to IgH. Our findings reveal peripheral B cells that have undergone both editing and CSR and show them to be common progenitors of CXP tumors. Our studies also reveal developmental stage-specific mechanisms of c-myc activation via IgH locus translocations. Thus, Xrcc4/p53-deficient pro–B lymphomas routinely activate c-myc by gene amplification, whereas Xrcc4/p53-deficient peripheral B cell lymphomas routinely ectopically activate a single c-myc copy.

Abbreviations used: A-EJ, alternative end-joining; AID, activation-induced cytidine deaminase; C-NHEJ, classical NHEJ; CSR, class switch recombination; DSB, double-strand break; FISH, fluorescence in situ hybridization; NHEJ, nonhomologous end-joining; QM, quasimonoclonal; RS, recombination signal sequence; SHM, somatic hypermutation; SKY, spectral karyotyping.

J.H. Wang and C.T. Yan contributed equally to this paper.

© 2008 Wang et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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B cells keep on editing
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