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

Georg Lenz, Inga Nagel, Reiner Siebert, Anna V. Roschke, Warren G Sanger, George W. Wright, Sandeep S. Dave, Bruce Tan, Hong Zhao, Andreas Rosenwald, Hans Konrad Muller-Hermelink, Randy D. Gascoyne, Elias Campo, Elaine S. Jaffe, Erlend B. Smeland, Richard I. Fisher, W. Michael Kuehl, Wing C. Chan, Louis M. Staudt

Research output: Contribution to journalArticle

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Abstract

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 Sγ 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.

Original languageEnglish (US)
Pages (from-to)633-643
Number of pages11
JournalJournal of Experimental Medicine
Volume204
Issue number3
DOIs
StatePublished - Mar 19 2007

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Lymphoma, Large B-Cell, Diffuse
Immunoglobulin Isotypes
Genetic Recombination
B-Lymphocytes
B-Cell Lymphoma
Genetic Translocation
Neoplasms
Germinal Center
Southern Blotting
Sequence Analysis
Clone Cells
Chromosomes
Mutation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma. / Lenz, Georg; Nagel, Inga; Siebert, Reiner; Roschke, Anna V.; Sanger, Warren G; Wright, George W.; Dave, Sandeep S.; Tan, Bruce; Zhao, Hong; Rosenwald, Andreas; Muller-Hermelink, Hans Konrad; Gascoyne, Randy D.; Campo, Elias; Jaffe, Elaine S.; Smeland, Erlend B.; Fisher, Richard I.; Kuehl, W. Michael; Chan, Wing C.; Staudt, Louis M.

In: Journal of Experimental Medicine, Vol. 204, No. 3, 19.03.2007, p. 633-643.

Research output: Contribution to journalArticle

Lenz, G, Nagel, I, Siebert, R, Roschke, AV, Sanger, WG, Wright, GW, Dave, SS, Tan, B, Zhao, H, Rosenwald, A, Muller-Hermelink, HK, Gascoyne, RD, Campo, E, Jaffe, ES, Smeland, EB, Fisher, RI, Kuehl, WM, Chan, WC & Staudt, LM 2007, 'Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma', Journal of Experimental Medicine, vol. 204, no. 3, pp. 633-643. https://doi.org/10.1084/jem.20062041
Lenz, Georg ; Nagel, Inga ; Siebert, Reiner ; Roschke, Anna V. ; Sanger, Warren G ; Wright, George W. ; Dave, Sandeep S. ; Tan, Bruce ; Zhao, Hong ; Rosenwald, Andreas ; Muller-Hermelink, Hans Konrad ; Gascoyne, Randy D. ; Campo, Elias ; Jaffe, Elaine S. ; Smeland, Erlend B. ; Fisher, Richard I. ; Kuehl, W. Michael ; Chan, Wing C. ; Staudt, Louis M. / Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma. In: Journal of Experimental Medicine. 2007 ; Vol. 204, No. 3. pp. 633-643.
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AU - Roschke, Anna V.

AU - Sanger, Warren G

AU - Wright, George W.

AU - Dave, Sandeep S.

AU - Tan, Bruce

AU - Zhao, Hong

AU - Rosenwald, Andreas

AU - Muller-Hermelink, Hans Konrad

AU - Gascoyne, Randy D.

AU - Campo, Elias

AU - Jaffe, Elaine S.

AU - Smeland, Erlend B.

AU - Fisher, Richard I.

AU - Kuehl, W. Michael

AU - Chan, Wing C.

AU - Staudt, Louis M.

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N2 - 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 Sγ 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.

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