The Journal of Experimental Medicine
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Published online March 12, 2007
doi:10.1084/jem.20062041
The Journal of Experimental Medicine, Vol. 204, No. 3, 633-643
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Lenz et al.
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ARTICLE

 Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell–like diffuse large B cell lymphoma

Georg Lenz1, Inga Nagel5, Reiner Siebert5, Anna V. Roschke3, Warren Sanger6, George W. Wright4, Sandeep S. Dave1, Bruce Tan1, Hong Zhao1, Andreas Rosenwald7, Hans Konrad Muller-Hermelink7, Randy D. Gascoyne8, Elias Campo9, Elaine S. Jaffe2, Erlend B. Smeland10, Richard I. Fisher11,12, W. Michael Kuehl3, Wing C. Chan6, and Louis M. Staudt1

1 Metabolism Branch, 2 Laboratory of Pathology, 3 Genetics Branch, Center for Cancer Research, and 4 Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892
5 Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel, D-24105 Kiel, Germany
6 Department of Pathology and Department of Microbiology, University of Nebraska Medical Center, Omaha, NE 68198
7 Department of Pathology, University of Würzburg, 97070 Würzburg, Germany
8 British Columbia Cancer Agency, Vancouver, British Columbia V5Z 4E6, Canada
9 Hospital Clinic, University of Barcelona, 08007 Barcelona, Spain
10 Department of Immunology, Rikshospitalet-Radiumhospitalet Medical Center, 0805 Oslo, Norway
11 Southwest Oncology Group, San Antonio, TX 78245
12 James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, NY 14627

CORRESPONDENCE Louis M. Staudt: lstaudt{at}mail.nih.gov

To elucidate the mechanisms underlying chromosomal translocations in diffuse large B cell lymphoma (DLBCL), we investigated the nature and extent of immunoglobulin class switch recombination (CSR) in these tumors. We used Southern blotting to detect legitimate and illegitimate CSR events in tumor samples of the activated B cell–like (ABC), germinal center B cell–like (GCB), and primary mediastinal B cell lymphoma (PMBL) subgroups of DLBCL. The frequency of legitimate CSR was lower in ABC DLBCL than in GCB DLBCL and PMBL. In contrast, ABC DLBCL had a higher frequency of internal deletions within the switch µ (Sµ) region compared with GCB DLBCL and PMBL. ABC DLBCLs also had frequent deletions within S{gamma} and other illegitimate switch recombinations. Sequence analysis revealed ongoing Sµ deletions within ABC DLBCL tumor clones, which were accompanied by ongoing duplications and activation-induced cytidine deaminase–dependent somatic mutations. Unexpectedly, short fragments derived from multiple chromosomes were interspersed within Sµ in one case. These findings suggest that ABC DLBCLs have abnormalities in the regulation of CSR that could predispose to chromosomal translocations. Accordingly, aberrant switch recombination was responsible for translocations in ABC DLBCLs involving BCL6, MYC, and a novel translocation partner, SPIB.

Abbreviations used: ABC, activated B cell–like; AID, activation-induced cytidine deaminase; CSR, class switch recombination; DLBCL, diffuse large B cell lymphoma; FISH, fluorescence in situ hybridization; GCB, germinal center B cell–like; MALT, mucosa-associated lymphoid tissue; PMBL, primary mediastinal B cell lymphoma.


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