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

Abstract 

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.

Abbreviations: AML, acute myeloid leukemia, ALL, acute lymphoblastic leukemia, MDS, myelodysplastic syndrome, MSP, methylation-specific PCR, FAB, French–American–British, DFS, disease free survival, APL, acute promyelocytic leukemia

Keywords: Methylation, Acute myeloid leukemia, p15^INK4b, E-cadherin