TitleMDS and secondary AML display unique patterns and abundance of aberrant DNA methylation.
Publication TypeJournal Article
Year of Publication2009
AuthorsFigueroa, Maria E., Skrabanek Lucy, Li Yushan, Jiemjit Anchalee, Fandy Tamer E., Paietta Elisabeth, Fernandez Hugo, Tallman Martin S., Greally John M., Carraway Hetty, Licht Jonathan D., Gore Steven D., and Melnick Ari
Date Published2009 Oct 15
KeywordsAntigens, CD34, Azacitidine, Bone Marrow Cells, DNA Methylation, DNA, Neoplasm, Enzyme Inhibitors, Female, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Leukemia, Myeloid, Acute, Male, MAP Kinase Signaling System, Myelodysplastic Syndromes, Neoplasms, Second Primary, Promoter Regions, Genetic, Time Factors, Wnt Proteins

<p>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.</p>

Alternate JournalBlood
PubMed ID19652201
PubMed Central IDPMC2765680
Grant ListR21 CA110507 / CA / NCI NIH HHS / United States
R01 CA125635 / CA / NCI NIH HHS / United States
U01 CA070095 / CA / NCI NIH HHS / United States
U54 CA143876 / CA / NCI NIH HHS / United States
R01 HD044078 / HD / NICHD NIH HHS / United States
U01CA70095 / CA / NCI NIH HHS / United States
U10 CA021115 / CA / NCI NIH HHS / United States
U54 CA143876-01 / CA / NCI NIH HHS / United States
K24 CA111717 / CA / NCI NIH HHS / United States
CA21115 / CA / NCI NIH HHS / United States
U24 CA114737 / CA / NCI NIH HHS / United States
R01 CA104348 / CA / NCI NIH HHS / United States