p16INK4a loss and sensitivity in KSHV associated primary effusion lymphoma.
The Kaposi's Sarcoma associated Herpes virus (KSHV) encodes two genes with the potential to affect the activity of the retinoblastoma protein (Rb). Open reading frame (orf) 72 encodes a D type cyclin (kcyc) that can elicit p16INK4a resistant cdk activity and orf73 encodes the latency associated nuclear antigen (LNA) that can bind Rb and neutralize E2F regulation. This indicates that, like papilloma and adenovirus associated malignancies, those associated with KSHV are defective with respect to their Rb pathway. To address this we investigated whether KSHV associated primary effusion lymphoma (PEL) derived cell lines are resistant to growth inhibition by p16INK4a. We provide evidence that ectopic expression of p16INK4a in these cells causes an Rb dependent G1 cell cycle block. Importantly, endogenous p16INK4a expression is not detected in six PEL derived cell lines and four primary PEL samples and examination of the p16INK4a locus shows deletion in two out of six and hypermethylation in four out of six PEL lines. Treatment of the latter with the demethylating agent 5'-aza-2' deoxycytidine leads to re-expression of p16INK4a protein. Taken together these results suggest that p16INK4a loss may be a cellular change frequently associated with PEL. They furthermore argue that despite the presence of KSHV DNA and expression of a latent gene program Rb function is intact in PEL.
Platt
Georgina
G
Centre for Molecular and Cell Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London, UK.
Carbone
Antonino
A
Mittnacht
Sibylle
S
D000256:Adenoviridae / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015153:Blotting, Western; D018899:CpG Islands; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D019175:DNA Methylation; D017931:DNA Primers / Q000737:chemistry; D000077209:Decitabine; D015536:Down-Regulation; D017353:Gene Deletion; D019288:Herpesvirus 8, Human / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D009154:Mutation; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured
D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D012334:RNA, Neoplasm; D016160:Retinoblastoma Protein; D000077209:Decitabine; D018844:Cyclin-Dependent Kinases; D001374:Azacitidine