title: Genomic impact of transient low-dose decitabine treatment on primary AML cells.
abstract: Acute myeloid leukemia (AML) is characterized by dysregulated gene expression and abnormal patterns of DNA methylation; the relationship between these events is unclear. Many AML patients are now being treated with hypomethylating agents, such as decitabine (DAC), although the mechanisms by which it induces remissions remain unknown. The goal of this study was to use a novel stromal coculture assay that can expand primary AML cells to identify the immediate changes induced by DAC with a dose (100nM) that decreases total 5-methylcytosine content and reactivates imprinted genes (without causing myeloid differentiation, which would confound downstream genomic analyses). Using array-based technologies, we found that DAC treatment caused global hypomethylation in all samples (with a preference for regions with higher levels of baseline methylation), yet there was limited correlation between changes in methylation and gene expression. Moreover, the patterns of methylation and gene expression across the samples were primarily determined by the intrinsic properties of the primary cells, rather than DAC treatment. Although DAC induces hypomethylation, we could not identify canonical target genes that are altered by DAC in primary AML cells, suggesting that the mechanism of action of DAC is more complex than previously recognized.
authors.affiliation: Departments of Pathology and Immunology and.
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Klco
authors.forename: David H
authors.initials: DH
authors.lastname: Spencer
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Lamprecht
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Sarkaria
authors.forename: Todd
authors.initials: T
authors.lastname: Wylie
authors.forename: Vincent
authors.initials: V
authors.lastname: Magrini
authors.forename: Jasreet
authors.initials: J
authors.lastname: Hundal
authors.forename: Jason
authors.initials: J
authors.lastname: Walker
authors.forename: Nobish
authors.initials: N
authors.lastname: Varghese
authors.forename: Petra
authors.initials: P
authors.lastname: Erdmann-Gilmore
authors.forename: Cheryl F
authors.initials: CF
authors.lastname: Lichti
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Meyer
authors.forename: R Reid
authors.initials: RR
authors.lastname: Townsend
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D018899:CpG Islands / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D015894:Genome, Human / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D051379:Mice; D046228:Microarray Analysis; D061251:Primary Cell Culture; D013997:Time Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D001374:Azacitidine