Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 205, Issue 13, Pages 3079-3090Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20082271
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Funding
- National Institutes of Health (NIH) [5P01 CA92625]
- NRSA [T32 CA7008]
- Leukemia and Lymphoma Society (LLS)
- Howard Hughes Medical Institute
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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.
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