Journal
BLOOD
Volume 114, Issue 13, Pages 2764-2773Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-02-203547
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Funding
- NCI NIH HHS [R21 CA110507, U01CA70095, K24 CA111717, R01 CA125635, U01 CA070095] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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Sequential administration of DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors has demonstrated clinical efficacy in patients with hematologic malignancies. However, the mechanism behind their clinical efficacy remains controversial. In this study, the methylation dynamics of 4 TSGs (p15(INK4B), CDH-1, DAPK-1, and SOCS-1) were studied in sequential bone marrow samples from 30 patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who completed a minimum of 4 cycles of therapy with 5-azacytidine and entinostat. Reversal of promoter methylation after therapy was observed in both clinical responders and nonresponders across all genes. There was no association between clinical response and either baseline methylation or methylation reversal in the bone marrow or purified CD34(+) population, nor was there an association with change in gene expression. Transient global hypomethylation was observed in samples after treatment but was not associated with clinical response. Induction of histone H3/H4 acetylation and the DNA damage-associated variant histone gamma-H2AX was observed in peripheral blood samples across all dose cohorts. In conclusion, methylation reversal of candidate TSGs during cycle 1 of therapy was not predictive of clinical response to combination epigenetic therapy. This trial is registered with http://www.clinicaltrials.gov under NCT00101179. (Blood. 2009;114:2764-2773)
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