Hypermethylation of the tumor suppressor gene PRDM1/Blimp-1 supports a pathogenetic role in EBV-positive Burkitt lymphoma.
PRDM1/Blimp-1 is a tumor suppressor gene in the activated B-cell subtype of diffuse large B-cell lymphomas. Its inactivation contributes to pathogenesis in this setting by impairing terminal B-cell differentiation induced by constitutive nuclear factor-κB activation. The role of PRDM1 in Burkitt lymphoma (BL) lymphomagenesis is not known. Here we identified hypermethylation of the promoter region and exon 1 of PRDM1 in all six Epstein-Barr virus (EBV)-positive BL cell lines and 12 of 23 (52%) primary EBV-positive BL or BL-related cases examined, but in none of the EBV-negative BL cell lines or primary tumors that we assessed, implying a tumor suppressor role for PRDM1 specifically in EBV-associated BL. A direct induction of PRDM1 hypermethylation by EBV is unlikely, as PRDM1 hypermethylation was not observed in EBV-immortalized B lymphoblastoid cell lines. Treatment of EBV-positive BL cells with 5' azacytidine resulted in PRDM1 induction associated with PRDM1 demethylation, consistent with transcriptional silencing of PRDM1 as a result of DNA methylation. Overexpression of PRDM1 in EBV-positive BL cell lines resulted in cell cycle arrest. Our results expand the spectrum of lymphoid malignancies in which PRDM1 may have a tumor suppressor role and identify an epigenetic event that likely contributes to the pathogenesis of BL.
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
T
T
Zhang
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
J
J
Ma
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
K
K
Nie
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
J
J
Yan
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
Y
Y
Liu
Consultoria em Patologia, Botucatu, São Paulo, Brazil.
C E
CE
Bacchi
Consultoria em Patologia, Botucatu, São Paulo, Brazil.
E M
EM
Queiroga
Consultoria em Patologia, Botucatu, São Paulo, Brazil.
G
G
Gualco
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, The Penn State Hershey Cancer Institute, Hershey, PA, USA.
J T
JT
Sample
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
A
A
Orazi
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
D M
DM
Knowles
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
W
W
Tam
D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D008297:Male; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1