Mechanisms promoting translocations in editing and switching peripheral B cells

Nature. 2009 Jul 9;460(7252):231-6. doi: 10.1038/nature08159.


Variable, diversity and joining gene segment (V(D)J) recombination assembles immunoglobulin heavy or light chain (IgH or IgL) variable region exons in developing bone marrow B cells, whereas class switch recombination (CSR) exchanges IgH constant region exons in peripheral B cells. Both processes use directed DNA double-strand breaks (DSBs) repaired by non-homologous end-joining (NHEJ). Errors in either V(D)J recombination or CSR can initiate chromosomal translocations, including oncogenic IgH locus (Igh) to c-myc (also known as Myc) translocations of peripheral B cell lymphomas. Collaboration between these processes has also been proposed to initiate translocations. However, the occurrence of V(D)J recombination in peripheral B cells is controversial. Here we show that activated NHEJ-deficient splenic B cells accumulate V(D)J-recombination-associated breaks at the lambda IgL locus (Igl), as well as CSR-associated Igh breaks, often in the same cell. Moreover, Igl and Igh breaks are frequently joined to form translocations, a phenomenon associated with specific Igh-Igl co-localization. Igh and c-myc also co-localize in these cells; correspondingly, the introduction of frequent c-myc DSBs robustly promotes Igh-c-myc translocations. Our studies show peripheral B cells that attempt secondary V(D)J recombination, and determine a role for mechanistic factors in promoting recurrent translocations in tumours.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism*
  • Cytidine Deaminase / deficiency
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / metabolism
  • DNA Breaks, Double-Stranded
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Rearrangement, B-Lymphocyte / genetics*
  • Genes, Immunoglobulin / genetics*
  • Genes, myc / genetics
  • Homeodomain Proteins / metabolism
  • Immunoglobulin Class Switching / genetics*
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin kappa-Chains / genetics
  • Immunoglobulin lambda-Chains / genetics
  • Integrases / genetics
  • Integrases / metabolism
  • Interphase
  • Lymphocyte Activation
  • Male
  • Mice
  • Receptors, Complement 3d / genetics
  • Recombination, Genetic / genetics
  • Spleen / cytology
  • Spleen / immunology
  • Translocation, Genetic / genetics*


  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Immunoglobulin Heavy Chains
  • Immunoglobulin kappa-Chains
  • Immunoglobulin lambda-Chains
  • Rag2 protein, mouse
  • Receptors, Complement 3d
  • XRCC4 protein, mouse
  • RAG-1 protein
  • Cre recombinase
  • Integrases
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase