title: The DNA demethylating agent decitabine activates the TRAIL pathway and induces apoptosis in acute myeloid leukemia.
abstract: Although epigenetic drugs have been approved for use in selected malignancies, there is significant need for a better understanding of their mechanism of action. Here, we study the action of a clinically approved DNA-methyltransferase inhibitor - decitabine (DAC) - in acute myeloid leukemia (AML) cells. At low doses, DAC treatment induced apoptosis of NB4 Acute Promyelocytic Leukemia (APL) cells, which was associated with the activation of the extrinsic apoptotic pathway. Expression studies of the members of the Death Receptor family demonstrated that DAC induces the expression of TNF-related apoptosis-inducing ligand (TRAIL). Upregulation of TRAIL, upon DAC treatment, was associated with specific epigenetic modifications induced by DAC in the proximity of the TRAIL promoter, as demonstrated by DNA demethylation, increased DNaseI sensitivity and histone acetylation of a non-CpG island, CpG-rich region located 2kb upstream to the transcription start site. Luciferase assay experiments showed that this region behave as a DNA methylation sensitive transcriptional regulatory element. The CpG regulatory element was also found methylated in samples derived from APL patients. These findings have been confirmed in the non-APL, AML Kasumi cell line, suggesting that this regulatory mechanism may be extended to other AMLs. Our study suggests that DNA methylation is a regulatory mechanism relevant for silencing of the TRAIL apoptotic pathway in leukemic cells, and further elucidates the mechanism by which epigenetic drugs mediate their anti-leukemic effects.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Matías
authors.initials: M
authors.lastname: Soncini
authors.forename: Fabio
authors.initials: F
authors.lastname: Santoro
authors.forename: Arantxa
authors.initials: A
authors.lastname: Gutierrez
authors.forename: Gianmaria
authors.initials: G
authors.lastname: Frigè
authors.forename: Mauro
authors.initials: M
authors.lastname: Romanenghi
authors.forename: Oronza A
authors.initials: OA
authors.lastname: Botrugno
authors.forename: Isabella
authors.initials: I
authors.lastname: Pallavicini
authors.forename: PierGiuseppe
authors.initials: P
authors.lastname: Pelicci
authors.forename: Luciano
authors.initials: L
authors.lastname: Di Croce
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*
chemical_list: D056572:Histone Deacetylase Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077209:Decitabine; D001374:Azacitidine