Methylation of p15(INK4b) and E-cadherin genes is independently correlated with poor prognosis in acute myeloid leukemia.

Hypermethylation of CpG islands is a common mechanism by which tumor suppressor genes are inactivated. The tumor suppressor gene p15(INK4b) is important component of cell cycles, whereas E-cadherin gene is often termed a metastasis suppressor gene. We have studied the feasibility of detecting tumor-associated aberrant p15(INK4b) and E-cadherin methylation in acute myeloid leukemia (AML) using methylation-specific PCR. Aberrant methylation of p15(INK4b) was detected in 31 of 61 (51%) AML patients. On the other hand, E-cadherin hypermethylation was detected in 36 of 61 (56%) AML patients. We have examined the methylation pattern of these genes and the prognosis in AML patients using a log-rank test. Methylation of p15(INK4b) gene significantly correlated with prognosis (p=0.0012), and methylation of E-cadherin gene more significantly correlated with prognosis (p=0.0004). When both were methylated, there was even more significant unfavorable prognosis compared to either of the methylated genes (p<0.0001). We interpret these data to mean that dysfunction of the cell cycle and/or the cell-cell adhesion molecule plays a role in the pathogenesis of acute myeloid leukemia and that analysis of the methylation of p15(INK4b) and E-cadherin genes can provide clinically important evidence on which to base treatment.