Abstract
Primary effusion lymphoma (PEL) is a lymphoproliferative disease of B-cell origin that is associated with HHV-8 infection. PEL cells harbor a non-B, non-T phenotype and lack significant surface immunoglobulin (Ig) expression, a characteristic that has not been fully explained. In the present study, we demonstrate that PEL cells constitutively express interferon regulatory factor (IRF)-4, a transcription factor that regulates the activity of the immunoglobulin light-chain enhancer elements lambdaB and kappaE3' through binding to a composite Ets-IRF site. IRF-4 activity requires its physical interaction with PU.1, an Ets family member involved in the activation of genes essential for B-cell development. However, in PEL-derived B-cell lines, PU.1 expression was completely abrogated; expression of the B cell specific transcription factor Oct-2, which is known to regulate PU.1 expression, was also abolished. Moreover, the B-cell-specific coactivator of octamer factors, BOB-1/OcaB, was expressed at very decreased levels in PEL cells. Ectopic expression of Oct-2 was able to fully restore PU.1 promoter activity in the PEL cell line BCBL-1, while PU.1 expression also reconstituted the activity of the lambdaB Ets-IRF site. In addition, protein levels of BSAP/Pax-5 and IRF-8/ICSBP were undetectable in PEL cells. The pattern of transcription factor ablation observed in PEL was found to be comparable to that observed in classical Hodgkin's disease-derived cell lines, which also lack B-cell-specific surface markers. These observations indicate that disruption of the B-cell-specific transcriptional program is likely to contribute to the incomplete B-cell phenotype characteristic of PEL cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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B-Lymphocytes / metabolism*
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Body Fluids
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Burkitt Lymphoma / genetics
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Burkitt Lymphoma / metabolism
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Burkitt Lymphoma / pathology
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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Enhancer Elements, Genetic
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Gene Expression Regulation, Neoplastic*
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Herpesviridae Infections / genetics*
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Herpesviridae Infections / metabolism
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Herpesviridae Infections / pathology
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Herpesvirus 8, Human / isolation & purification*
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Hodgkin Disease / genetics
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Hodgkin Disease / metabolism
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Hodgkin Disease / pathology
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Humans
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Immunoglobulin Light Chains / genetics
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Interferon Regulatory Factors
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Lymphoma, B-Cell / genetics*
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Lymphoma, B-Cell / metabolism
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Lymphoma, B-Cell / pathology
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Lymphoma, B-Cell / virology
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics*
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Octamer Transcription Factor-2
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PAX5 Transcription Factor
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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RNA, Messenger / biosynthesis
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RNA, Neoplasm / biosynthesis
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Recombinant Fusion Proteins / physiology
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Repressor Proteins / biosynthesis
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Repressor Proteins / genetics
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
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Transcription Factors / biosynthesis
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Transcription Factors / genetics*
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Transcription, Genetic*
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Transfection
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Tumor Virus Infections / genetics*
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Tumor Virus Infections / metabolism
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Tumor Virus Infections / pathology
Substances
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DNA-Binding Proteins
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Immunoglobulin Light Chains
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Interferon Regulatory Factors
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Neoplasm Proteins
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Octamer Transcription Factor-2
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PAX5 Transcription Factor
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PAX5 protein, human
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POU2AF1 protein, human
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POU2F2 protein, human
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Proto-Oncogene Proteins
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RNA, Messenger
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RNA, Neoplasm
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Recombinant Fusion Proteins
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Repressor Proteins
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Trans-Activators
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Transcription Factors
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interferon regulatory factor-4
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interferon regulatory factor-8
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proto-oncogene protein Spi-1