Methylation profiling in acute myeloid leukemia

Aberrant methylation of multiple CpG islands has been described in acute my eloid leukemia (AML), but it is not known whether these are independent eve nts or whether they reflect specific methylation defects in a subset of cas es. To study this issue, the methylation status of 14 promoter-associated C pG islands was analyzed in 36 cases of AML previously characterized for est rogen-receptor methylation (ERM). Cases with methylation density of 10% or greater were considered positive. Seventeen cases (47%) were ERM+ while 19 cases were ERM-. Hypermethylation of any of the following, p15, p16, CACNA1 g, MINT1, MINT2, MDR1, THBS1, and PTC1 (2 promoters), was relatively infreq uent (6% to 31% of patients). For each of these CpG islands, the methylatio n density was positively correlated with ERM density (rank order correlatio n coefficients, 0.32-0.59; 2-tailed P less than or equal to .058 for each g ene). Hypermethylation of MYOD1, PITX2, GPR37, and SDC4 was frequently foun d in AML (47% to 64% of patients). For each of these genes as well, methyla tion density was positively correlated with ERM density (correlation coeffi cients 0.43 to 0.69, P less than or equal to .0087 for each gene). MLH1 was unmethylated in all cases. Hypermethylation of p15, MDR1, and SDC4 correla ted with reduced levels of expression. There was an inverse correlation bet ween age and the number of genes methylated (P=.0030). It was concluded tha t CpG-island methylation in AML results from methylation defects in subsets of cases. These results have potential implications for the classification and prognosis of AML and for the identification of patients who may benefi t from treatment with methylation inhibitors. (Blood, 2001;97:2823-2829) (C ) 2001 by The American Society of Hematology.