PRDI-BF1/Blimp1 is a zinc finger transcriptional repressor expressed in post-germinal center (GC) B cells and required for terminal B cell differentiation.

The PRDM1/BLIMP 1 locus lies on chromosomal band 6q21–q22.1, a region frequently deleted in B-cell non-Hodgkin’s lymphomas suggesting the existence of one or more tumor suppressor loci (

Gaidano et al,
Blood
80
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1781
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1992
). To test whether genetic alterations affecting the BLIMP1 gene may be involved in DLBCL pathogenesis, we performed PCR amplification and direct sequencing of the BLIMP1 coding sequences in 136 cases, including 20 cell lines and 116 primary biopsies. Gene expression profiling analysis using the Affymetrix Gene Chip system was used in 93 cases to classify them as germinal center B-cell like (GCB, N=38), activated B-cell like (ABC, N=35) and type III (N=20). Nonsense mutations were found in 7 of 136 cases. Four of these mutations generated premature stop codons, predicting severely truncated proteins of 61 to 244 aminoacids; in three cases, a single bp substitution affecting the exon 2 splice donor site led to insertion of 101 nucleotides from intron 3 and a premature stop codon. One primary tumor case carried a mutation within the intron 3 splice acceptor site, and one cell line displayed a gene rearrangement in one allele with deletion of the second allele. Strikingly, 6 of the 7 nonsense mutations identified segregated with the ABC phenotype (the remaining case was not profiled), suggesting that these alterations may be common and specific in this subtype of DLBCL (6/35, 17%). In addition, missense mutations generating aminoacid substitutions were found in 8 additional cases, and complete lack of Blimp-1 protein expression was found in most ABC-type DLBCL cases. These observations suggest that inactivation of the BLIMP1 gene may occur also by other mechanisms, including the generation of dominant negative mutants, chromosomal deletion or epigenetic silencing, in a large fraction of DLBCL. Functional studies are currently being performed to corroborate these data. Overall, these results suggest that BLIMP1 may act as a tumor suppressor gene, whose loss or inactivation may contribute to lymphomagenesis by blocking post-GC differentiation of B cells toward plasma cells.

Topics:
diffuse large b-cell lymphoma, genes, positive regulatory domain i-binding factor 1, amino acids, biopsy, dna microarrays, gene expression profiling, hodgkin's disease, leukemogenesis, lymphoma

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2005, The American Society of Hematology
2005
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