Methylation of the ABL1 promoter in chronic myelogenous leukemia: Lack of prognostic significance

The BCR-ABL chromosomal translocation is a central event in the pathogenesi s of chronic myelogenous leukemia (CML). One of the ABL1 promoters (Pa) and the coding region of the gene are usually translocated intact to the BCR l ocus, but the translocated promoter appears to be silent in most cases. Rec ently, hypermethylation of Pa was demonstrated in CML and was proposed to m ark advanced stages of the disease. To study this issue, we measured Pa met hylation in CML using Southern blot analysis. Of 110 evaluable samples, 23 (21%) had no methylation, 17 (15%) had minimal (<15%) methylation, 12 (11%) had moderate methylation (15% to 25%), and 58 (53%) had high levels of met hylation (>25%) at the ABL1 locus. High methylation was more frequent in ad vanced cases of CML. Among the 76 evaluable patients in early chronic phase (ECP), a major cytogenetic response with interferon-based therapy was obse rved in 14 of 34 patients with high methylation compared with 19 of 42 amon g the others (41% v 45%; P value not significant). At a median follow-up of 7 years, there was no significant difference in survival by ABL1 methylati on category. Among patients who achieved a major cytogenetic response, low levels of methylation were associated with a trend towards improved surviva l, but this trend did not reach statistical significance. Thus, Pa methylat ion in CML is associated with disease progression but does not appear to pr edict for survival or response to interferon-based therapy. (C) 1999 by The American Society of Hematology.