Genome-wide methylation profiling in decitabine-treated patients with acute myeloid leukemia.
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, low-dose (20 mg/m(2) per day for 10 days) decitabine, a DNA hypomethylating 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.
Division of Hematology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, 460 W 12th Ave, Columbus, OH 43210, USA.
Pearlly
P
Yan
David
D
Frankhouser
Mark
M
Murphy
Hok-Hei
HH
Tam
Benjamin
B
Rodriguez
John
J
Curfman
Michael
M
Trimarchi
Susan
S
Geyer
Yue-Zhong
YZ
Wu
Susan P
SP
Whitman
Klaus
K
Metzeler
Alison
A
Walker
Rebecca
R
Klisovic
Samson
S
Jacob
Michael R
MR
Grever
John C
JC
Byrd
Clara D
CD
Bloomfield
Ramiro
R
Garzon
William
W
Blum
Michael A
MA
Caligiuri
Ralf
R
Bundschuh
Guido
G
Marcucci
D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D000077209:Decitabine; D005260:Female; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic
D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D000077209:Decitabine; D001374:Azacitidine