Genome-wide methylation profiling in decitabine-treated patients with acute myeloid leukemia

Pearlly Yan, David Frankhouser, Mark Murphy, Hok Hei Tam, Benjamin Rodriguez, John Curfman, Michael Trimarchi, Susan Geyer, Yue Zhong Wu, Susan P. Whitman, Klaus Metzeler, Alison Walker, Rebecca Klisovic, Samson Jacob, Michael R. Grever, John C. Byrd, Clara D. Bloomfield, Ramiro Garzon, William Blum, Michael A. CaligiuriRalf Bundschuh, Guido Marcucci

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2466-2474
Number of pages9
JournalBlood
Volume120
Issue number12
DOIs
StatePublished - Sep 20 2012

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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