1. In primary effusion lymphoma cells, MYB transcriptional repression is associated with v-FLIP expression during latent KSHV infection while both v-FLIP and v-GPCR become involved during the lytic cycle
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Françoise Valensi, Antoine Gessain, Christophe Nicot, Hittu Matta, Renaud Mahieux, Preet M. Chaudhary, Vincent Lacoste, Jean Gabarre, Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Department of Microbiology, Molecular genetics and Immunology, University of Kansas Medical Center [Lawrence], Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Division of Hematology-Oncology and the Hillman Cancer Center, University of Pittsburgh Medical Center, This work was supported by a grant from l'Association de Recherche sur le Cancer (ARC) and from la Fondation de France to RM and grants from NIH (CA85177 and CA124621) to PMC. VL and CN were supported by a bourse Pasteur‐Weissman and la Ligue Nationale Contre le Cancer respectively. RM was supported by a bourse Roux, from the Institut Pasteur and by INSERM., We thank Dr D. Gonzalez‐Dunia, J.S. Seeler and C. Royer‐Leveau for their help. We are indebted to Drs P. Charneau, J. Golay, N. Rice, L. Boxer, P. Murphy and W.C. Greene for generous gifts of reagents essential to the realization of this study. We thank Pr O. Hermine for providing us with some PEL fresh samples, and Dr Timothy Stinear for his critical comments., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Kansas Medical Center [Kansas City, KS, USA], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Pittsburgh Medical Center [Pittsburgh, PA, États-Unis] (UPMC), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), University of Kansas Medical Center, Laboratoire d'hématologie ( ERL 8254 ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP]
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non-Hodgkinlymphoma ,Transcription, Genetic ,Genes, myb ,[SDV]Life Sciences [q-bio] ,viruses ,CASP8 and FADD-Like Apoptosis Regulating Protein ,Gene Expression ,MESH : Sarcoma, Kaposi ,MESH : Herpesvirus 8, Human ,MESH: Virus Activation ,Receptors, G-Protein-Coupled ,Transduction (genetics) ,molecular studies ,0302 clinical medicine ,MESH: Lymphoma, Non-Hodgkin/virology ,Transduction, Genetic ,MESH: Viral Proteins/metabolism ,Virus latency ,MESH : Virus Latency ,MYB ,MESH : Cell Transformation, Viral ,Viral G-Protein Coupled Receptor ,MESH : Viral Proteins ,MESH: Lymphoma, AIDS-Related/metabolism ,Lymphoma, AIDS-Related ,Regulation of gene expression ,MESH : Trans-Activators ,0303 health sciences ,Lymphoma, Non-Hodgkin ,MESH: Virus Latency ,NF-kappa B ,Hematology ,Transfection ,MESH : Immediate-Early Proteins ,MESH: Transduction, Genetic ,MESH: Gene Expression Regulation, Viral ,MESH: Sarcoma, Kaposi/metabolism ,MESH: Herpesvirus 8, Human/physiology ,Virus Latency ,3. Good health ,Lytic cycle ,MESH: Cell Transformation, Viral ,MESH : NF-kappa B ,MESH : Genes, myb ,030220 oncology & carcinogenesis ,Herpesvirus 8, Human ,MESH : Virus Activation ,MESH : Receptors, G-Protein-Coupled ,Primary effusion lymphoma ,MESH : Transfection ,MESH: NF-kappa B/metabolism ,Gene Expression Regulation, Viral ,MESH: Cell Line, Tumor ,MESH: Gene Expression ,animal structures ,MESH : Transduction, Genetic ,MESH : Lymphoma, AIDS-Related ,Biology ,MESH : Gene Expression Regulation, Viral ,Immediate-Early Proteins ,Proto-Oncogene Proteins c-myb ,Viral Proteins ,03 medical and health sciences ,MESH: Receptors, G-Protein-Coupled/metabolism ,MESH: Sarcoma, Kaposi/virology ,MESH: Trans-Activators/metabolism ,Cell Line, Tumor ,medicine ,nuclear factor-jB ,Humans ,MESH : Lymphoma, Non-Hodgkin ,MESH: CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism ,Sarcoma, Kaposi ,030304 developmental biology ,B cells ,MESH: Humans ,MESH : Cell Line, Tumor ,herpes virus ,MESH: Lymphoma, AIDS-Related/virology ,MESH: Transcription, Genetic ,MESH: Transfection ,MESH: Immediate-Early Proteins/metabolism ,MESH : Humans ,MESH: Proto-Oncogene Proteins c-myb/analysis ,MESH : Transcription, Genetic ,Kaposi sarcoma ,MESH : CASP8 and FADD-Like Apoptosis Regulating Protein ,Cell Transformation, Viral ,medicine.disease ,MESH : Proto-Oncogene Proteins c-myb ,MESH : Gene Expression ,MESH: Genes, myb ,Trans-Activators ,Cancer research ,MESH: Lymphoma, Non-Hodgkin/metabolism ,Virus Activation - Abstract
International audience; Primary effusion lymphoma (PEL) is a rare, distinct subtype of non-Hodgkin lymphoma, which is associated with Kaposi sarcoma-associated herpesvirus (KSHV) infection. Although MYB levels are high in most neoplastic B cells, we found that, unexpectedly, both PEL cells and uncultured PEL patients' samples contained very low levels of MYB mRNA when compared to B-cell leukaemia samples obtained from KSHV(-) patients. These results were further confirmed at the protein level. Both latent viral FLICE inhibitory protein (v-FLIP) and early lytic viral G protein coupled receptor (v-GPCR) KSHV proteins were found to activate nuclear factor (NF)-kappaB and transrepress a MYB promoter reporter construct. In contrast, a dominant negative inhibitor of NF-kappaB (IkappaB-alpha) mutant prevented v-FLIP and v-GPCR from inhibiting MYB functions while a v-GPCR mutant that was impaired for NF-kappaB activation could not repress the MYB construct. Transduction of a v-FLIP expressing vector or stable transfection of v-GPCR both resulted in a marked downregulation of the endogenous MYB protein expression. However, MYB expression transactivated the lytic switch Replication and Transcription Activator (RTA) promoter in transient transfection assays. Taken together, our results demonstrate that, contrary to a number of other haematological malignancies, MYB expression is not required for PEL cell proliferation. Repressing MYB expression also helps in maintaining the virus in latency.
- Published
- 2007
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