Aberrant CpG island methylation in acute myeloid leukemia is accentuated at relapse.
DNA methylation of CpG islands around gene transcription start sites results in gene silencing and plays a role in leukemia pathophysiology. Its impact in leukemia progression is not fully understood. We performed genomewide screening for methylated CpG islands and identified 8 genes frequently methylated in leukemia cell lines and in patients with acute myeloid leukemia (AML): NOR1, CDH13, p15, NPM2, OLIG2, PGR, HIN1, and SLC26A4. We assessed the methylation status of these genes and of the repetitive element LINE-1 in 30 patients with AML, both at diagnosis and relapse. Abnormal methylation was found in 23% to 83% of patients at diagnosis and in 47% to 93% at relapse, with CDH13 being the most frequently methylated. We observed concordance in methylation of several genes, confirming the presence of a hypermethylator pathway in AML. DNA methylation levels increased at relapse in 25 of 30 (83%) patients with AML. These changes represent much larger epigenetic dysregulation, since methylation microarray analysis of 9008 autosomal genes in 4 patients showed hypermethylation ranging from 5.9% to 13.6% (median 8.3%) genes at diagnosis and 8.0% to 15.2% (median 10.6%) genes in relapse (P < .001). Our data suggest that DNA methylation is involved in AML progression and provide a rationale for the use of epigenetic agents in remission maintenance.
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Heike
H
Kroeger
Jaroslav
J
Jelinek
Marcos R H
MR
Estécio
Rong
R
He
Kimie
K
Kondo
Woonbok
W
Chung
Li
L
Zhang
Lanlan
L
Shen
Hagop M
HM
Kantarjian
Carlos E
CE
Bueso-Ramos
Jean-Pierre J
JP
Issa
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D018450:Disease Progression; D052138:Genes, Neoplasm; D023281:Genomics; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology*; D008875:Middle Aged; D012008:Recurrence