1. Howard Hughes Medical Institute,
2. The Children's Hospital,
3. Immune Disease Institute,
4. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
5. Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
6. Division of Rheumatology, Allergy and Immunology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
7. These authors contributed equally to this work.
8. Present address: Ali A. Zarrin, Immunology Discovery Group, Genentech, South San Francisco, California 94080, USA.

Correspondence to: Frederick W. Alt^1,2,3,4 Correspondence and requests for materials should be addressed to F.W.A. (Email: alt@enders.tch.harvard.edu).

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.

1. Howard Hughes Medical Institute,
2. The Children's Hospital,
3. Immune Disease Institute,
4. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
5. Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
6. Division of Rheumatology, Allergy and Immunology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
7. These authors contributed equally to this work.
8. Present address: Ali A. Zarrin, Immunology Discovery Group, Genentech, South San Francisco, California 94080, USA.

Correspondence to: Frederick W. Alt^1,2,3,4 Correspondence and requests for materials should be addressed to F.W.A. (Email: alt@enders.tch.harvard.edu).

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