Journal
BLOOD
Volume 114, Issue 16, Pages 3448-3458Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-01-200519
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Funding
- American Society of Hematology Fellow Scholar Award [R01 CA104348, R01 HD044078, R21 CA110507, K24 CA111717, U01CA70095, U24 CA114737]
- National Cancer Institute [CA21115]
- Chemotherapy Foundation
- Samuel Waxman Cancer Research Foundation
- GP Foundation
- Burroughs Welcome Clinical Scientist Award
- Leukemia & Lymphoma Society Scholar Award
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Increasing evidence shows aberrant hypermethylation of genes occurring in and potentially contributing to pathogenesis of myeloid malignancies. Several of these diseases, such as myelodysplastic syndromes (MDSs), are responsive to DNA methyltransferase inhibitors. To determine the extent of promoter hypermethylation in such tumors, we compared the distribution of DNA methylation of 14 000 promoters in MDS and secondary acute myeloid leukemia (AML) patients enrolled in a phase 1 trial of 5-azacytidine and the histone deacetylase inhibitor entinostat against de novo AML patients and normal CD34(+) bone marrow cells. The MDS and secondary AML patients displayed more extensive aberrant DNA methylation involving thousands of genes than did the normal CD34(+) bone marrow cells or de novo AML blasts. Aberrant methylation in MDS and secondary AML tended to affect particular chromosomal regions, occurred more frequently in Alu-poor genes, and included prominent involvement of genes involved in the WNT and MAPK signaling pathways. DNA methylation was also measured at days 15 and 29 after the first treatment cycle. DNA methylation was reversed at day 15 in a uniform manner throughout the genome, and this effect persisted through day 29, even without continuous administration of the study drugs. This trial was registered at www.clinicaltrials.gov as J0443. (Blood. 2009;114:3448-3458)
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