TY - JOUR
T1 - Genome-wide methylation profiling in decitabine-treated patients with acute myeloid leukemia
AU - Yan, Pearlly
AU - Frankhouser, David
AU - Murphy, Mark
AU - Tam, Hok Hei
AU - Rodriguez, Benjamin
AU - Curfman, John
AU - Trimarchi, Michael
AU - Geyer, Susan
AU - Wu, Yue Zhong
AU - Whitman, Susan P.
AU - Metzeler, Klaus
AU - Walker, Alison
AU - Klisovic, Rebecca
AU - Jacob, Samson
AU - Grever, Michael R.
AU - Byrd, John C.
AU - Bloomfield, Clara D.
AU - Garzon, Ramiro
AU - Blum, William
AU - Caligiuri, Michael A.
AU - Bundschuh, Ralf
AU - Marcucci, Guido
PY - 2012/9/20
Y1 - 2012/9/20
N2 - The outcome of older (≥ 60 years) acute myeloid leukemia (AML) patients is poor, and novel treatments are needed. In a phase 2 trial for older AML patients, lowdose (20 mg/m2 per day for 10 days) decitabine, a DNAhypomethylating azanucleoside, produced 47% complete response rate with an excellent toxicity profile. To assess the genome-wide activity of decitabine, we profiled pretreatment and post treatment (day 25/course 1) methylomes of marrow samples from patients (n = 16) participating in the trial using deep-sequencing analysis of methylated DNA captured by methyl-binding protein (MBD2). Decitabine significantly reduced global methylation compared with pretreatment baseline (P = .001). Percent marrow blasts did not correlate with global methylation levels, suggesting that hypomethylation was related to the activity of decitabine rather than to a mere decrease in leukemia burden. Hypomethylation occurred predominantly in CpG islands and CpG island-associated regions (P ranged from .03 to .04) A significant concentration (P < .001) of the hypomehtylated CpG islands was found in chromosome subtelomeric regions, suggesting a differential activity of decitabine in distinct chromosome regions. Hypermethylation occurred much less frequently than hypomethylation and was associated with low CpG content regions. Decitabine-related methylation changes were concordant with those previously reported in distinct genes. In summary, our study supports the feasibility of methylome analyses as a pharmacodynamic endpoint for hypomethylating therapies.
AB - The outcome of older (≥ 60 years) acute myeloid leukemia (AML) patients is poor, and novel treatments are needed. In a phase 2 trial for older AML patients, lowdose (20 mg/m2 per day for 10 days) decitabine, a DNAhypomethylating azanucleoside, produced 47% complete response rate with an excellent toxicity profile. To assess the genome-wide activity of decitabine, we profiled pretreatment and post treatment (day 25/course 1) methylomes of marrow samples from patients (n = 16) participating in the trial using deep-sequencing analysis of methylated DNA captured by methyl-binding protein (MBD2). Decitabine significantly reduced global methylation compared with pretreatment baseline (P = .001). Percent marrow blasts did not correlate with global methylation levels, suggesting that hypomethylation was related to the activity of decitabine rather than to a mere decrease in leukemia burden. Hypomethylation occurred predominantly in CpG islands and CpG island-associated regions (P ranged from .03 to .04) A significant concentration (P < .001) of the hypomehtylated CpG islands was found in chromosome subtelomeric regions, suggesting a differential activity of decitabine in distinct chromosome regions. Hypermethylation occurred much less frequently than hypomethylation and was associated with low CpG content regions. Decitabine-related methylation changes were concordant with those previously reported in distinct genes. In summary, our study supports the feasibility of methylome analyses as a pharmacodynamic endpoint for hypomethylating therapies.
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U2 - 10.1182/blood-2012-05-429175
DO - 10.1182/blood-2012-05-429175
M3 - Article
C2 - 22786882
AN - SCOPUS:84866551964
SN - 0006-4971
VL - 120
SP - 2466
EP - 2474
JO - Blood
JF - Blood
IS - 12
ER -