Aberrant methylation of multiple tumor suppressor genes in acute myeloid leukemia

Hypermethylator phenotype, a propensity of tumors to incur nonrandom concurrent methylation, has been described in several tumors, including acute myeloid leukemia (AML). More recent studies identified methylation of other tumor suppressor genes, DAP-kinase and SOCS1, singly in AML. We therefore assessed the methylation status of these genes concurrently with other known targets of methylation. We used methylation-specific PCR or COBRA to determine the extent of methylation of 10 genes in 28 AML samples from Turkey. In addition to DAP-kinase and SOCS1, we included ER, p15, and E-cadherin (reported to be frequently methylated) as well as p16, GSTP1, and HIC1 (reported as rarely methylated). We also included RARbeta and p73 for which only minimal data in AML is available. All samples were methylated at least in one locus and all except one demonstrated methylation of DAP-kinase, SOCS1, p15, and/or ER. DAP-kinase is the most frequently methylated gene in both pediatric (70%) and adult AML (55%). RARbeta is methylated in 18% and p73 in 10% of AMLs. Methylation of E-cadherin and RARbeta occurs preferentially in AMLs with high methylation index (MI), while epigenetic lesions in SOCS1, DAP-kinase, and p15 appear to be independent. MI may be age-dependent, with a peak in young adults. FAB M3 demonstrated a higher extent of methylation than M2/M4. This study provides an impetus for larger studies to define if the extent and pattern of methylation in subgroups of AML are clinically relevant.