title: Combined deletion of Xrcc4 and Trp53 in mouse germinal center B cells leads to novel B cell lymphomas with clonal heterogeneity.
abstract: BACKGROUND
  Activated B lymphocytes harbor programmed DNA double-strand breaks (DSBs) initiated by activation-induced deaminase (AID) and repaired by non-homologous end-joining (NHEJ). While it has been proposed that these DSBs during secondary antibody gene diversification are the primary source of chromosomal translocations in germinal center (GC)-derived B cell lymphomas, this point has not been directly addressed due to the lack of proper mouse models.
  
  
  METHODS
  In the current study, we establish a unique mouse model by specifically deleting a NHEJ gene, Xrcc4, and a cell cycle checkpoint gene, Trp53, in GC B cells, which results in the spontaneous development of B cell lymphomas that possess features of GC B cells.
  
  
  RESULTS
  We show that these NHEJ deficient lymphomas harbor translocations frequently targeting immunoglobulin (Ig) loci. Furthermore, we found that Ig translocations were associated with distinct mechanisms, probably caused by AID- or RAG-induced DSBs. Intriguingly, the AID-associated Ig loci translocations target either c-myc or Pvt-1 locus whereas the partners of RAG-associated Ig translocations scattered randomly in the genome. Lastly, these NHEJ deficient lymphomas harbor complicated genomes including segmental translocations and exhibit a high level of ongoing DNA damage and clonal heterogeneity.
  
  
  CONCLUSIONS
  We propose that combined NHEJ and p53 defects may serve as an underlying mechanism for a high level of genomic complexity and clonal heterogeneity in cancers.
authors.affiliation: Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, 12800 E. 19th Ave, Mail Stop 8333, Aurora, CO, 80045, USA.|Department of Biomedical Research, National Jewish Health, Denver, CO, 80206, USA.
authors.forename: Zhangguo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, 12800 E. 19th Ave, Mail Stop 8333, Aurora, CO, 80045, USA.
authors.forename: Mihret T
authors.initials: MT
authors.lastname: Elos
authors.affiliation: Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, 12800 E. 19th Ave, Mail Stop 8333, Aurora, CO, 80045, USA.
authors.forename: Sawanee S
authors.initials: SS
authors.lastname: Viboolsittiseri
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Gowan
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO, 80206, USA.|Integrated Center for Genes, Environment and Health, National Jewish Health, Denver, CO, 80206, USA.
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Leach
authors.affiliation: Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, 12800 E. 19th Ave, Mail Stop 8333, Aurora, CO, 80045, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rice
authors.affiliation: Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, 12800 E. 19th Ave, Mail Stop 8333, Aurora, CO, 80045, USA.
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Eder
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Jones
authors.affiliation: Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, 12800 E. 19th Ave, Mail Stop 8333, Aurora, CO, 80045, USA. jing.wang@ucdenver.edu.|Department of Biomedical Research, National Jewish Health, Denver, CO, 80206, USA. jing.wang@ucdenver.edu.
authors.forename: Jing H
authors.initials: JH
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D001483:Base Sequence; D002478:Cells, Cultured; D002999:Clone Cells / Q000378:metabolism; D003564:Cytidine Deaminase / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D018858:Germinal Center / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D016393:Lymphoma, B-Cell / Q000235:genetics*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D016159:Tumor Suppressor Protein p53; C511788:XRCC4 protein, mouse; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase