title: Epigenetic control of NF-κB-dependent FAS gene transcription during progression of myelodysplastic syndromes.
abstract: The death domain containing TNF receptor 6 (CD95/Fas) is a direct target for the NF-κB transcription factor and is repressed in solid tumors such as colon carcinomas. Previously, we reported that the Fas death receptor, while overexpressed in low-risk myelodysplastic syndromes (MDS), becomes undetectable on CD34(+) progenitors when the disease progresses to secondary acute myeloid leukemia (AML). This study determined the interplay between NF-κB and Fas during MDS progression. We first observed that Fas was induced by TNF-α in the HL60 cell line. In these cells, p65 (RELA) was associated with the FAS promoter, and inhibition of the NF-κB pathway by an IKKα inhibitor (BAY11-7082) or lentiviral expression of a nondegradable mutant of IκBα (IκSR) blocked Fas expression. In contrast, TNF-α failed to induce Fas expression in the colon carcinoma cell line SW480, due to hypermethylation of the FAS promoter. Azacitidine rescued p65 binding on FAS promoter in vitro, and subsequently Fas expression in SW480 cells. Furthermore, inhibition of the NF-κB pathway decreased the expression of Fas in MDS CD45(lo)CD34(+) bone marrow cells. However, despite the nuclear expression of p65, Fas was often low on CD45(lo)CD34(+) AML cells. TNF-α failed to stimulate its expression, while azacitidine efficiently rescued p65 binding and Fas reexpression. Overall, these data suggest that DNA methylation at NF-κB sites is responsible for FAS gene silencing.
authors.affiliation: Département d'Immunologie-Hématologie, Institut Cochin, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ettou
authors.forename: Catherine
authors.initials: C
authors.lastname: Humbrecht
authors.forename: Blandine
authors.initials: B
authors.lastname: Benet
authors.forename: Katy
authors.initials: K
authors.lastname: Billot
authors.forename: Diane
authors.initials: D
authors.lastname: d'Allard
authors.forename: Virginie
authors.initials: V
authors.lastname: Mariot
authors.forename: Michele
authors.initials: M
authors.lastname: Goodhardt
authors.forename: Olivier
authors.initials: O
authors.lastname: Kosmider
authors.forename: Patrick
authors.initials: P
authors.lastname: Mayeux
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.forename: Michaela
authors.initials: M
authors.lastname: Fontenay
mesh_terms: D001374:Azacitidine / Q000494:pharmacology; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D044127:Epigenesis, Genetic / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology*; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D013450:Sulfones / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; C491901:FAS protein, human; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; D019014:fas Receptor; D001374:Azacitidine