Epigenetic differences in cytogenetically normal versus abnormal acute myeloid leukemia

Methylation of tumor suppression genes (TSGs) is common in myeloid malignancies. However, application of this as a molecular marker for risk stratification in patients with AML is limited. To elucidate the impact of patterns of TSG methylation on outcome in cytogenetically normal patients, 106 samples from patients with normal cytogenetic AML were evaluated for methylation of 12 genes by MSP. For sake of comparison, samples from patients with AML and abnormal cytogenetics (n = 63) were also evaluated. Methylation frequencies in the whole group (n = 169) were similar to previous reports for CDH1 (31%), ER (31%), FHIT (9%), p15(INK4b) (44%), p73 (25%) and SOCS1 (75%). Methylation of CTNNA1 was observed in 10%, CEBP-alpha in 16%, CEBP-delta in 2%, MLH1 in 24%, MGMT in 11% and DAPK in 2% of AML samples. We find that DNA methylation was more prevalent in patients with normal compared to karyotypically abnormal AML for most genes; CEBP alpha (20% vs 9%), CTNNA1 (14% vs 4%) and ER (41% vs 19%) (p < 0.05 for all comparisons). In contrast, p73 was more frequently methylated in patients with karyotypic abnormalities (17% vs 38%; p < 0.05), perhaps due to specific silencing of the pro-apoptotic promoter shifting p73 gene expression to the anti-apoptotic transcript. In AML patients with normal cytogenetics, TSG methylation was not associated with event free or overall survival in a multivariate analysis. In patients with AML, TSG methylation is more frequent in patients with normal karyotype than those with karyotypic abnormalities but does not confer independent prognostic information for patients with normal cytogenetics.