DNA methylation of multiple promoter-associated CpG islands in adult acute lymphocytic leukemia

Purpose: Aberrant methylation of promoter-associated CpG islands is an epigenetic oncogenic mechanism. The objective of this study was to define the methylation characteristics of patients with acute lymphocytic leukemia (ALL). Experimental Design: Using bisulfite-PCR followed by restriction enzyme digestion (COBRA), we have analyzed the methylation status of 10 promoter-associated CpG islands in 80 untreated adult patients with ALL. Results: Mean methylation density of MDR1, THBS2, MYF3, ER, p15, THBS1, CD10, C-ABL, and p16 was 24.5%, 20.8%, 17.6%, 16.1%, 11.3%, 8.9%, 4.5%, 3.7%, and 1.3% respectively. p73 was methylated in 17 of 80 cases (21.2%). A total of 86.2% of the cases had methylation of at least one gene, and 42.5% of the cases had methylation of three or more genes. MDR1 methylation was inversely correlated with age (P = 0.01). CD10 methylation inversely correlated with CD10 expression (P = 0.0001). Methylation of MDR1 and THBS1 was inversely associated with the presence of the Philadelphia chromosome, whereas C-ABL methylation correlated with the presence of the p210 variant of the Philadelphia chromosome. In univariate analysis, methylation of THBS1 was associated with a favorable outcome (P = 0.02), whereas methylation of p73, p15, and C-ABL was associated with a trend toward worse prognosis. Conclusions: Aberrant DNA methylation of promoter associated CpG islands is very common in adult ALL and potentially defines subgroups with distinct clinical and biological characteristics.