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*H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
Cancer Biology Ph.D. Program,
Department of Oncologic Sciences, and
Department of Molecular Medicine, University of South Florida, Tampa, FL 33612
The human positive regulatory domain I-binding factor 1 (PRDI-BF1) and its murine homolog Blimp-1 promote differentiation of mature B cells into Ab-secreting plasma cells. In contrast, ectopic expression of PRDI-BF1 in lymphoma cells can lead to inhibition of proliferation or apoptosis. However, little is currently known about the regulation of PRDM1, the gene encoding PRDI-BF1. This report establishes that in lymphoma cells stimulation through the BCR rapidly induces endogenous PRDM1 at the level of transcription with minor changes in mRNA stability. The induced PRDM1-encoded protein localizes to its target genes in vivo and suppresses their expression. In vivo genomic footprinting of the PRDM1 promoter in unstimulated lymphoma and myeloma cells reveals multiple common in vivo occupied elements throughout the promoter. Further functional and structural analysis of the promoter reveals that the promoter is preloaded and poised for activation in the B cell lines. The transcription factor PU.1 is shown to be required for the BCR-induced expression of PRDM1 in lymphoma cells and in PU.1-positive myeloma cells. Activation of PRDM1 is associated with loss of the corepressor transducin-like enhancer of split 4 from the PU.1 complex. These findings indicate that PRDM1 is poised for activation in lymphoma cells and therefore may be a potential therapeutic target to inhibit lymphoma cell proliferation and survival.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants CA114504 and CA080990.
2 These authors contributed equally to the work presented in this report.
3 Current address: National Institute of Environmental Health Sciences, Laboratory of Molecular Carcinogenesis, 111 TW Alexander Drive, Room C310, Research Triangle Park, NC 27709.
4 Address correspondence and reprint requests to Dr. Kenneth L. Wright, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, MRC-4 East, Tampa, FL 33612. E-mail address: ken.wright{at}moffitt.org
5 Abbreviations used in this paper: PRDI-BF1, positive regulatory domain I-binding factor 1; BSAP, B cell lineage-specific activator protein; FWD, forward; REV, reverse; siRNA, small interfering RNA; ChIP, chromatin immunoprecipitation; UTR, untranslated region; TLE4, transducin-like enhancer of split 4; CBP, CREB-binding protein; BCL6, B cell lymphoma 6.
6 The online version of this article contains supplemental material.
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