MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation.
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.
Figueroa
Maria E
ME
Department of Medicine (Hematology Oncology Division), Weill Cornell Medical College, New York, NY 10065, USA. amm2014@med.cornell.edu
Skrabanek
Lucy
L
Li
Yushan
Y
Jiemjit
Anchalee
A
Fandy
Tamer E
TE
Paietta
Elisabeth
E
Fernandez
Hugo
H
Tallman
Martin S
MS
Greally
John M
JM
Carraway
Hetty
H
Licht
Jonathan D
JD
Gore
Steven D
SD
Melnick
Ari
A
D018952:Antigens, CD34; D001374:Azacitidine / Q000008:administration & dosage*; D001854:Bone Marrow Cells / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000378:metabolism; D016609:Neoplasms, Second Primary / Q000188:drug therapy* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D013997:Time Factors; D051153:Wnt Proteins / Q000378:metabolism
D018952:Antigens, CD34; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D051153:Wnt Proteins; D006655:Histone Deacetylases; D001374:Azacitidine