Genomic impact of transient low-dose decitabine treatment on primary AML cells

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...

Celý popis

Uloženo v:

Podrobná bibliografie
Vydáno v:	Blood Ročník 121; číslo 9; s. 1633
Hlavní autoři:	Klco, Jeffery M, Spencer, David H, Lamprecht, Tamara L, Sarkaria, Shawn M, Wylie, Todd, Magrini, Vincent, Hundal, Jasreet, Walker, Jason, Varghese, Nobish, Erdmann-Gilmore, Petra, Lichti, Cheryl F, Meyer, Matthew R, Townsend, R Reid, Wilson, Richard K, Mardis, Elaine R, Ley, Timothy J
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 28.02.2013
Témata:	Animals Antimetabolites, Antineoplastic - administration & dosage Antimetabolites, Antineoplastic - pharmacology Azacitidine - administration & dosage Azacitidine - analogs & derivatives Azacitidine - pharmacology Cells, Cultured CpG Islands - drug effects CpG Islands - genetics Decitabine DNA Methylation - drug effects DNA Methylation - genetics Dose-Response Relationship, Drug Gene Expression Profiling Gene Expression Regulation, Leukemic - drug effects Genome, Human - drug effects Humans Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - pathology Mice Microarray Analysis Primary Cell Culture Time Factors
ISSN:	1528-0020, 1528-0020
On-line přístup:	Zjistit podrobnosti o přístupu
Tagy:	Přidat tag Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!

Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Undefined-1 ObjectType-Feature-3 content type line 23
ISSN:	1528-0020 1528-0020
DOI:	10.1182/blood-2012-09-459313