Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma.
PR domain containing 1 with zinc finger domain (PRDM1)/B lymphocyte-induced maturation protein 1 (BLIMP1) is a transcriptional repressor expressed in a subset of germinal center (GC) B cells and in all plasma cells, and required for terminal B cell differentiation. The BLIMP1 locus lies on chromosome 6q21-q22.1, a region frequently deleted in B cell lymphomas, suggesting that it may harbor a tumor suppressor gene. We report here that the BLIMP1 gene is inactivated by structural alterations in 24% (8 out of 34) activated B cell-like diffuse large cell lymphoma (ABC-DLBCL), but not in GC B cell-like (n = 0/37) or unclassified (n = 0/21) DLBCL. BLIMP1 alterations included gene truncations, nonsense mutations, frameshift deletions, and splice site mutations that generate aberrant transcripts encoding truncated BLIMP1 proteins. In all cases studied, both BLIMP1 alleles were inactivated by deletions or mutations. Furthermore, most non-GC type DLBCL cases (n = 20/26, 77%) lack BLIMP1 protein expression, despite the presence of BLIMP1 mRNA. These results indicate that a sizable fraction of ABC-DLBCL carry an inactive BLIMP1 gene, and suggest that the same gene is inactivated by epigenetic mechanisms in an additional large number of cases. These findings point to a role for BLIMP1 as a tumor suppressor gene, whose inactivation may contribute to lymphomagenesis by blocking post-GC differentiation of B cells toward plasma cells.
Institute for Cancer Genetics and 2The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
Laura
L
Pasqualucci
Mara
M
Compagno
Jane
J
Houldsworth
Stefano
S
Monti
Adina
A
Grunn
Subhadra V
SV
Nandula
Jon C
JC
Aster
Vundavally V
VV
Murty
Margaret A
MA
Shipp
Riccardo
R
Dalla-Favera
D001402:B-Lymphocytes / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D018389:Codon, Nonsense; D016368:Frameshift Mutation; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D016393:Lymphoma, B-Cell / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D010950:Plasma Cells / Q000473:pathology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D022821:RNA Splice Sites / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*
D018389:Codon, Nonsense; D022821:RNA Splice Sites; D012097:Repressor Proteins; D014157:Transcription Factors; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1