Aberrant CpG island methylation in acute myeloid leukemia is accentuated at relapse

Abstract

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. (Blood. 2008;112:1366-1373)

DNA Methylation in Acute Leukemia

“…Using the same platform, Wilop and colleagues found a gain of overall methylation in 32 AML patient samples (Wilop et al, 2011). The methylation pattern was maintained at relapse with increased density and extended to addition genes, consistent with the previous studies (Agrawal et al, 2007;Kroeger et al, 2008). These observations provided a strong scientific basis for DNA methylation to be used as a biomarker for diagnosis, minimal residual disease detection and clinical follow-up in AML patients.…”

Quantitative DNA methylation predicts survival in adult acute myeloid leukemia

“…7 Because DNA methylation is recognized as a key regulatory element of gene expression, [12][13][14] these findings point to a potential pathogenic role of aberrant DNA methylation patterns in distinct subgroups of AML patients. 15 In accordance, aberrant methylation patterns have already been described in AML, 16,17 and recent studies further support a crucial role of epigenetic changes (epigenetics) in leukemia biology, [18][19][20][21] as well as a potential impact in patient outcome. 22 However, so far a lack of suitable technologies to quantitatively evaluate promoter methylation of numerous genes in large sample sets has prevented extensive exploration of the role of DNA methylation in hematologic malignancies and its impact in outcome prediction.…”

Gene-specific and global methylation patterns predict outcome in patients with acute myeloid leukemia

“…25 In AML, a decrease in global DNA methylation at relapse compared with diagnosis was observed in one study; however, these patients were selected on the grounds of having relapsed, which makes comparisons with our study difficult. 26 Mechanistically, global DNA hypomethylation may have a role in cancerogenesis through increased genomic instability, activation of oncogenes or retrotransposons. 27 The reason for the increased CR rates in patients with global hypomethylation observed in our study is unclear.…”