Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching
The Rockefeller University Press, 2008
Online
academicJournal
Zugriff:
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.
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Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching
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Autor/in / Beteiligte Person: | Alimzhanov, Marat B. ; Coakley, Kristen M. ; Alt, Frederick W. ; Wang, Jing ; Gostissa, Monica ; Datta, Abhishek ; Murphy, Michael C. ; Rajewsky, Klaus ; Manis, John P. ; Yan, Catherine T. |
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Veröffentlichung: | The Rockefeller University Press, 2008 |
Medientyp: | academicJournal |
ISSN: | 0022-1007 (print) |
DOI: | 10.1084/jem.20082271 |
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