Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma.
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.
Lenz
Georg
G
Metabolism Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Nagel
Inga
I
Siebert
Reiner
R
Roschke
Anna V
AV
Sanger
Warren
W
Wright
George W
GW
Dave
Sandeep S
SS
Tan
Bruce
B
Zhao
Hong
H
Rosenwald
Andreas
A
Muller-Hermelink
Hans Konrad
HK
Gascoyne
Randy D
RD
Campo
Elias
E
Jaffe
Elaine S
ES
Smeland
Erlend B
EB
Fisher
Richard I
RI
Kuehl
W Michael
WM
Chan
Wing C
WC
Staudt
Louis M
LM
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