Disruption of the B-cell specific transcriptional program in HHV-8 associated primary effusion lymphoma cell lines.
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.
Arguello
Meztli
M
Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
Sgarbanti
Marco
M
Hernandez
Eduardo
E
Mamane
Yael
Y
Sharma
Sonia
S
Servant
Marc
M
Lin
Rongtuan
R
Hiscott
John
J
D001402:B-Lymphocytes / Q000378:metabolism*; D001826:Body Fluids; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006566:Herpesviridae Infections / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019288:Herpesvirus 8, Human / Q000302:isolation & purification*; D006689:Hodgkin Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000235:genetics; D050835:Interferon Regulatory Factors; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D050813:Octamer Transcription Factor-2; D051757:PAX5 Transcription Factor; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection; D014412:Tumor Virus Infections / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4
D004268:DNA-Binding Proteins; D007147:Immunoglobulin Light Chains; D050835:Interferon Regulatory Factors; D009363:Neoplasm Proteins; D050813:Octamer Transcription Factor-2; D051757:PAX5 Transcription Factor; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4; C497281:PAX5 protein, human; C091546:POU2AF1 protein, human; C058435:POU2F2 protein, human