Mutational analysis of PRDM1 indicates a tumor-suppressor role in diffuse large B-cell lymphomas.
The PR (PRDI-BF1-RIZ) domain zinc finger protein 1 (PRDM1) is a transcription repressor with a pivotal role in plasma-cell differentiation. We identified clonal inactivating mutations in PRDM1 in the diffuse large B-cell lymphoma (DLBCL) cell line OCI-Ly3 and in 8 of 35 de novo clinical DLBCL samples. The mutational spectrum consists predominantly (7 cases) of single-nucleotide mutations affecting consensus splice donor sites, some of which are recurrent, that lead to splicing aberrations and premature translation termination. In 2 of these cases, point mutations appear to be caused by RNA editing with G-to-A and U-to-G conversions. Other mutations include frame-shift deletion and chromosomal inversion. Except for one mutant, which may act as a dominant-negative, all mutations are associated with either deletion or silencing of the paired PRDM1 allele. This study identifies PRDM1 inactivation as a recurrent genetic defect in DLBCL cells and establishes PRDM1 as a potential tumor suppressor gene in DLBCL. Moreover, it implies inhibition of terminal differentiation as a pathogenetic pathway in DLBCL, particularly for the activated B-cell-like DLBCL. It also demonstrates for the first time the potential role of RNA editing in lymphomagenesis.
Tam
Wayne
W
Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, K502A, 525 East 68th Street, New York, NY 10021, USA. wtam@med.cornell.edu
Gomez
Mario
M
Chadburn
Amy
A
Lee
Joong W
JW
Chan
Wing C
WC
Knowles
Daniel M
DM
D000595:Amino Acid Sequence; D001483:Base Sequence; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics; D017931:DNA Primers; D005091:Exons; D016147:Genes, Tumor Suppressor; D006801:Humans; D007438:Introns; D016393:Lymphoma, B-Cell / Q000235:genetics*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
D017931:DNA Primers; D012097:Repressor Proteins; D014157:Transcription Factors; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1