Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching.
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 Igkappa and Iglambda 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 Igkappa or Iglambda, with the latter fusing Iglambda 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.
Wang
Jing H
JH
Howard Hughes Medical Institute, Harvard Medical School, MA 02115, USA.
Alt
Frederick W
FW
Gostissa
Monica
M
Datta
Abhishek
A
Murphy
Michael
M
Alimzhanov
Marat B
MB
Coakley
Kristen M
KM
Rajewsky
Klaus
K
Manis
John P
JP
Yan
Catherine T
CT
D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000276:immunology*; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D015322:Gene Rearrangement, B-Lymphocyte; D050438:Genes, Immunoglobulin Heavy Chain; D006801:Humans; D017578:Immunoglobulin Class Switching; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000276:immunology; D011995:Recombination, Genetic; D016415:Sequence Alignment; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology
D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; C101467:XRCC4 protein, human