Mechanisms promoting translocations in editing and switching peripheral B cells

Jing H. Wang, Monica Gostissa, Catherine T. Yan, Peter Goff, Thomas Hickernell, Erica Hansen, Simone Difilippantonio, Duane R. Wesemann, Ali A. Zarrin, Klaus Rajewsky, Andre Nussenzweig and Frederick W. Alt ()
Additional contact information
Jing H. Wang: Howard Hughes Medical Institute,
Monica Gostissa: Howard Hughes Medical Institute,
Catherine T. Yan: Howard Hughes Medical Institute,
Peter Goff: Howard Hughes Medical Institute,
Thomas Hickernell: Howard Hughes Medical Institute,
Erica Hansen: Howard Hughes Medical Institute,
Simone Difilippantonio: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Duane R. Wesemann: Howard Hughes Medical Institute,
Ali A. Zarrin: Howard Hughes Medical Institute,
Klaus Rajewsky: Immune Disease Institute,
Andre Nussenzweig: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Frederick W. Alt: Howard Hughes Medical Institute,

Nature, 2009, vol. 460, issue 7252, 231-236

Abstract: Abstract 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.

Date: 2009
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DOI: 10.1038/nature08159

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