title: 5-azacytidine and decitabine exert proapoptotic effects on neoplastic mast cells: role of FAS-demethylation and FAS re-expression, and synergism with FAS-ligand.
abstract: Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are advanced hematopoietic neoplasms with poor prognosis. In these patients, neoplastic mast cells (MCs) are resistant against various drugs. We examined the effects of 2 demethylating agents, 5-azacytidine and decitabine on growth and survival of neoplastic MCs and the MC line HMC-1. Two HMC-1 subclones were used, HMC-1.1 lacking KIT D816V and HMC-1.2 exhibiting KIT D816V. Both agents induced apoptosis in HMC-1.1 and HMC-1.2 cells. Decitabine, but not 5-azacytidine, also produced a G(2)/M cell-cycle arrest in HMC-1 cells. Drug-induced apoptosis was accompanied by cleavage of caspase-8 and caspase-3 as well as FAS-demethylation and FAS-re-expression in neoplastic MCs. Furthermore, both demethylating agents were found to synergize with the FAS-ligand in inducing apoptosis in neoplastic MCs. Correspondingly, siRNA against FAS was found to block drug-induced expression of FAS and drug-induced apoptosis in HMC-1 cells. Neither 5-azacytidine nor decitabine induced substantial apoptosis or growth arrest in normal MCs or normal bone marrow cells. Together, 5-azacytidine and decitabine exert growth-inhibitory and proapoptotic effects in neoplastic MCs. These effects are mediated through "FAS-re-expression" and are augmented by the FAS-ligand. Whether epigenetic drugs produce antineoplastic effects in vivo in patients with ASM and MCL remains to be determined.
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, Austria
authors.forename: Viviane
authors.initials: V
authors.lastname: Ghanim
authors.forename: Harald
authors.initials: H
authors.lastname: Herrmann
authors.forename: Gerwin
authors.initials: G
authors.lastname: Heller
authors.forename: Barbara
authors.initials: B
authors.lastname: Peter
authors.forename: Emir
authors.initials: E
authors.lastname: Hadzijusufovic
authors.forename: Katharina
authors.initials: K
authors.lastname: Blatt
authors.forename: Karina
authors.initials: K
authors.lastname: Schuch
authors.forename: Sabine
authors.initials: S
authors.lastname: Cerny-Reiterer
authors.forename: Irina
authors.initials: I
authors.lastname: Mirkina
authors.forename: Heidrun
authors.initials: H
authors.lastname: Karlic
authors.forename: Winfried F
authors.initials: WF
authors.lastname: Pickl
authors.forename: Sabine
authors.initials: S
authors.lastname: Zöchbauer-Müller
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor / Q000187:drug effects; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D000077209:Decitabine; D004357:Drug Synergism; D053222:Fas Ligand Protein / Q000502:physiology; D005260:Female; D006801:Humans; D007946:Leukemia, Mast-Cell / Q000473:pathology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000473:pathology; D034721:Mastocytosis, Systemic / Q000473:pathology*; D008745:Methylation / Q000187:drug effects; D008875:Middle Aged; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000378:metabolism; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D019014:fas Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D019014:fas Receptor; D000077209:Decitabine; D019009:Proto-Oncogene Proteins c-kit; D001374:Azacitidine