Mechanisms promoting translocations in editing and switching peripheral B cells

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. B cell DNA breaks late The development of B cells in the immune system proceeds through several developmentalstages and in different compartments. Wang et al . show that two processes — editing and class switch recombination — widely thought to be separated temporally and spatially in the bone marrow and spleen respectively, can both occur in peripheral mature B cells. As these processes involve the formation of DNA double-strand breaks at different loci, rejoining of these breaks offers insight into the origin of chromosomal translocations observed in certain B cell lymphomas. Editing and class switch recombination, two processes in the development of B cells, are thought to be separated in the bone marrow and spleen, respectively. Errors in either of these processes can initiate chromosomal translocations, including those of B cell lymphomas, but collaboration between them may also initiate translocations. Here it is shown that both editing and class switch recombination can occur in peripheral B cells, offering insights into the origin of the transloc