title: Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma.
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 mu (Smu) region compared with GCB DLBCL and PMBL. ABC DLBCLs also had frequent deletions within Sgamma and other illegitimate switch recombinations. Sequence analysis revealed ongoing Smu 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 Smu 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.
authors.affiliation: Metabolism Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
authors.forename: Inga
authors.initials: I
authors.lastname: Nagel
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: Anna V
authors.initials: AV
authors.lastname: Roschke
authors.forename: Warren
authors.initials: W
authors.lastname: Sanger
authors.forename: George W
authors.initials: GW
authors.lastname: Wright
authors.forename: Sandeep S
authors.initials: SS
authors.lastname: Dave
authors.forename: Bruce
authors.initials: B
authors.lastname: Tan
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Hans Konrad
authors.initials: HK
authors.lastname: Muller-Hermelink
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.forename: Erlend B
authors.initials: EB
authors.lastname: Smeland
authors.forename: Richard I
authors.initials: RI
authors.lastname: Fisher
authors.forename: W Michael
authors.initials: WM
authors.lastname: Kuehl
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology*; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics / Q000276:immunology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000276:immunology*; D011995:Recombination, Genetic; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured