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

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Alimzhanov, Marat B.
Coakley, Kristen M.
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https://doi.org/10.1084/jem.20082271Metadata
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Wang, Jing H., Frederick W. Alt, Monica Gostissa, Abhishek Datta, Michael Murphy, Marat B. Alimzhanov, Kristen M. Coakley, Klaus Rajewsky, John P. Manis, and Catherine T. Yan. 2008. Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching. The Journal of Experimental Medicine 205(13): 3079-3090.Abstract
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 Igκ and Igλ 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 Igκ or Igλ, with the latter fusing Igλ 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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605230/pdf/Terms of Use
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