DNA methylation changes after 5-aza-2'-deoxycytidine therapy in patients with leukemia.
5-Aza-2'-deoxycytidine (decitabine) is postulated to have clinical activity in myeloid leukemias via its ability to inhibit DNA methylation. To study this, we examined DNA methylation in patients with leukemia treated with decitabine. Five days after the treatment, total genomic 5-methylcytosine/cytosine decreased on average by 14% (from 4.3% to 3.7%), whereas methylation of repetitive DNA elements showed a mean decrease of 9% and 16% for Alu and long interspersed nucleotide elements, respectively. Methylation decreased linearly with increasing doses between 5 and 20 mg/m(2)/d (r = 0.88; P = 0.05) but showed a plateau above that. Hypomethylation correlated with response in patients with acute myelogenous leukemia treated with low doses (5-20 mg/m(2)/d), but patients with chronic myelogenous leukemia treated with high doses (100-180 mg/m(2)/d) showed no such correlation. Aberrant methylation of p15 (>10%) was found in 27% of patients, and 80% of these showed a decrease by at least one third, but this did not correlate with response. The imprinted gene H19 showed little change in methylation after decitabine. In conclusion, we show dose-dependent hypomethylation after decitabine at low doses. Increasing the dose, which has been shown previously to result in a reduced response rate, was not accompanied by further hypomethylation.
Yang
Allen S
AS
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Doshi
Ketan D
KD
Choi
Sang-Woon
SW
Mason
Joel B
JB
Mannari
Rajan K
RK
Gharybian
Vazganush
V
Luna
Rene
R
Rashid
Asif
A
Shen
Lanlan
L
Estecio
Marcos R H
MR
Kantarjian
Hagop M
HM
Garcia-Manero
Guillermo
G
Issa
Jean-Pierre J
JP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D005260:Female; D016158:Genes, p53 / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; C094335:H19 long non-coding RNA; C489213:HOXA5 protein, human; D018398:Homeodomain Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D000077209:Decitabine; D001374:Azacitidine