Abstract
B-lymphocyte-induced maturation protein 1 (BLIMP1) exists as two major isoforms, α and β, which arise from alternate promoters. Inactivation of the full length BLIMP1α isoform is thought to contribute to B cell lymphomagenesis by blocking post-germinal centre (GC) B cell differentiation. In contrast, the shorter β isoform is functionally impaired and over-expressed in several haematological malignancies, including diffuse large B cell lymphomas (DLBCL). We have studied the influence on BLIMP1β expression of the Epstein-Barr virus (EBV), a human herpesvirus that is implicated in the pathogenesis of several GC-derived lymphomas, including a subset of DLBCL and Hodgkin’s lymphoma (HL). We show that BLIMP1β expression is increased following the EBV infection of normal human tonsillar GC B cells. We also show that this change in expression is accompanied by hypomethylation of the BLIMP1β-specific promoter. Furthermore, we confirmed previous reports that the BLIMP1β promoter is hypomethylated in DLBCL cell lines and show for the first time that BLIMP1β is hypomethylated in the Hodgkin/Reed-Sternberg (HRS) cells of HL. Our results provide evidence in support of a role for BLIMP1β in the pathogenesis of EBV-associated B cell lymphomas.
Highlights
The PRDM1 gene encodes two major isoforms, designated BLIMP1α and BLIMP1β, which arise from alternate promoters [1]
We first explored the impact of Epstein-Barr virus (EBV) infection on BLIMP1β expression in B cells
BLIMP1β expression in three LCLs derived from germinal centre (GC) B cells as well as in five LCLs established by the PBMCs of healthy donors
Summary
The PRDM1 gene encodes two major isoforms, designated BLIMP1α and BLIMP1β, which arise from alternate promoters [1]. The human MEL1/PRDM16 has two alternative protein forms, a long form, MEL1, and a short form, MEL1S The latter is over-expressed in leukaemia cells carrying the t(1;3) translocation [16,17]. The over-expression of BLIMP1β has been reported in multiple myeloma, DLBCL and in some T cell lymphomas [1,20,21,22]. DLBCL, the increased BLIMP1β mRNA levels are associated with hypomethylation of the BLIMP1β promoter [23] In both B- and T-cell lymphomas, BLIMP1β expression might be associated with in vitro resistance to chemotherapeutic agents [21,22]. A previous study reported that EBV infection of myeloma cells decreased BLIMP1 expression, but this study was not able to differentiate between the different isoforms [26]. We have investigated the influence of EBV on the expression and methylation status of the BLIMP1β isoform
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