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.
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20 February 2006
Brief Definitive Report|
February 21 2006
Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma
Laura Pasqualucci,
Laura Pasqualucci
1Institute for Cancer Genetics and
2The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032
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Mara Compagno,
Mara Compagno
1Institute for Cancer Genetics and
2The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032
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Jane Houldsworth,
Jane Houldsworth
3Laboratory of Cancer Genetics and the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
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Stefano Monti,
Stefano Monti
4Broad Institute, Massachusetts Institute of Technology, Cambridge, MA 02141
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Adina Grunn,
Adina Grunn
1Institute for Cancer Genetics and
2The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032
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Subhadra V. Nandula,
Subhadra V. Nandula
1Institute for Cancer Genetics and
2The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032
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Jon C. Aster,
Jon C. Aster
5Department of Pathology, Brigham and Women's Hospital and
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Vundavally V. Murty,
Vundavally V. Murty
1Institute for Cancer Genetics and
2The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032
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Margaret A. Shipp,
Margaret A. Shipp
6Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 12115
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Riccardo Dalla-Favera
Riccardo Dalla-Favera
1Institute for Cancer Genetics and
2The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032
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Laura Pasqualucci
1Institute for Cancer Genetics and
2The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032
Mara Compagno
1Institute for Cancer Genetics and
2The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032
Jane Houldsworth
3Laboratory of Cancer Genetics and the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
Stefano Monti
4Broad Institute, Massachusetts Institute of Technology, Cambridge, MA 02141
Adina Grunn
1Institute for Cancer Genetics and
2The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032
Subhadra V. Nandula
1Institute for Cancer Genetics and
2The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032
Jon C. Aster
5Department of Pathology, Brigham and Women's Hospital and
Vundavally V. Murty
1Institute for Cancer Genetics and
2The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032
Margaret A. Shipp
6Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 12115
Riccardo Dalla-Favera
1Institute for Cancer Genetics and
2The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032
CORRESPONDENCE Riccardo Dalla-Favera: [email protected]
Received:
November 01 2005
Accepted:
January 11 2006
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2006
J Exp Med (2006) 203 (2): 311–317.
Article history
Received:
November 01 2005
Accepted:
January 11 2006
Citation
Laura Pasqualucci, Mara Compagno, Jane Houldsworth, Stefano Monti, Adina Grunn, Subhadra V. Nandula, Jon C. Aster, Vundavally V. Murty, Margaret A. Shipp, Riccardo Dalla-Favera; Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma . J Exp Med 20 February 2006; 203 (2): 311–317. doi: https://doi.org/10.1084/jem.20052204
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