TY - JOUR
T1 - Genomic impact of transient low-dose decitabine treatment on primary AMLcells
AU - Klco, Jeffery M.
AU - Spencer, David H.
AU - Lamprecht, Tamara L.
AU - Sarkaria, Shawn M.
AU - Wylie, Todd
AU - Magrini, Vincent
AU - Hundal, Jasreet
AU - Walker, Jason
AU - Varghese, Nobish
AU - Erdmann-Gilmore, Petra
AU - Lichti, Cheryl F.
AU - Meyer, Matthew R.
AU - Townsend, R. Reid
AU - Wilson, Richard K.
AU - Mardis, Elaine R.
AU - Ley, Timothy J.
PY - 2013/2/28
Y1 - 2013/2/28
N2 - Acute myeloid leukemia (AML) is characterized by dysregulated gene expression and abnormal patterns of DNAmethylation; 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.
AB - Acute myeloid leukemia (AML) is characterized by dysregulated gene expression and abnormal patterns of DNAmethylation; 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.
UR - http://www.scopus.com/inward/record.url?scp=84876444289&partnerID=8YFLogxK
U2 - 10.1182/blood-2012-09-459313
DO - 10.1182/blood-2012-09-459313
M3 - Article
C2 - 23297133
AN - SCOPUS:84876444289
SN - 0006-4971
VL - 121
SP - 1633
EP - 1643
JO - Blood
JF - Blood
IS - 9
ER -