title: CpG methylation patterns and decitabine treatment response in acute myeloid leukemia cells and normal hematopoietic precursors.
abstract: The DNA hypomethylating drug decitabine maintains normal hematopoietic stem cell (HSC) self-renewal but induces terminal differentiation in acute myeloid leukemia (AML) cells. The basis for these contrasting cell fates, and for selective CpG hypomethylation by decitabine, is poorly understood. Promoter CpGs, with methylation measured by microarray, were classified by the direction of methylation change with normal myeloid maturation. In AML cells, the methylation pattern at maturation-responsive CpGs suggested at least partial maturation. Consistent with partial maturation, in gene expression analyses, AML cells expressed high levels of the key lineage-specifying factor CEBPA, but relatively low levels of the key late-differentiation driver CEBPE. In methylation analysis by mass spectrometry, CEBPE promoter CpGs that are usually hypomethylated during granulocyte maturation were significantly hypermethylated in AML cells. Decitabine-induced hypomethylation was greatest at these and other promoter CpGs that are usually hypomethylated with myeloid maturation, accompanied by cellular differentiation of AML cells. In contrast, decitabine-treated normal HSCs retained immature morphology, and methylation significantly decreased at CpGs that are less methylated in immature cells. High expression of lineage-specifying factor and aberrant epigenetic repression of some key late-differentiation driver genes distinguishes AML cells from normal HSCs, and could explain the contrasting differentiation and methylation responses to decitabine.
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA. saunthy@ccf.org
authors.forename: S
authors.initials: S
authors.lastname: Negrotto
authors.forename: K P
authors.initials: KP
authors.lastname: Ng
authors.forename: A M
authors.initials: AM
authors.lastname: Jankowska
authors.forename: J
authors.initials: J
authors.lastname: Bodo
authors.forename: B
authors.initials: B
authors.lastname: Gopalan
authors.forename: K
authors.initials: K
authors.lastname: Guinta
authors.forename: J C
authors.initials: JC
authors.lastname: Mulloy
authors.forename: E
authors.initials: E
authors.lastname: Hsi
authors.forename: J
authors.initials: J
authors.lastname: Maciejewski
authors.forename: Y
authors.initials: Y
authors.lastname: Saunthararajah
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001483:Base Sequence; D019070:Cell Lineage; D018899:CpG Islands; D019175:DNA Methylation; D017931:DNA Primers; D000077209:Decitabine; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D000077209:Decitabine; D001374:Azacitidine