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.
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.
Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, Paris, France.
Vincent
V
Lacoste
Christophe
C
Nicot
Antoine
A
Gessain
Françoise
F
Valensi
Jean
J
Gabarre
Hittu
H
Matta
Preet M
PM
Chaudhary
Renaud
R
Mahieux
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D015870:Gene Expression; D015967:Gene Expression Regulation, Viral; D020570:Genes, myb; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D016483:Lymphoma, AIDS-Related / Q000378:metabolism / Q000821:virology*; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism / Q000821:virology*; D016328:NF-kappa B / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb / Q000032:analysis; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000378:metabolism / Q000821:virology*; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D014162:Transfection; D014764:Viral Proteins / Q000378:metabolism; D014775:Virus Activation; D017735:Virus Latency
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D017874:Immediate-Early Proteins; D016328:NF-kappa B; D020598:Proto-Oncogene Proteins c-myb; D043562:Receptors, G-Protein-Coupled; C417604:Rta protein, Human herpesvirus 8; D015534:Trans-Activators; D014764:Viral Proteins