ABL1 methylation in Ph-positive ALL is exclusively associated with the P210 form of BCR-ABL

In human Ph-positive leukemia there is a clear association of different for ms of the BCR-ABL oncogene with distinct types of leukemia. The P190 form o f BCR-ABL is rarely observed in chronic myeloid leukemia (CML) but is prese nt in 50% of Ph-positive acute lymphoblastic leukemia (ALL). In contrast, t he P210 form is observed both in CML and 50% of Ph-positive ALL. Methylatio n of the proximal promoter of the ABL1 gene has been shown to he a nearly u niversal event associated with clinical progression of CML. This raises the question of whether methylation of the ABL1 promoter is an epigenetic modi fication also associated with Ph-positive ALL. To study this issue, we used methylation-specific PCR and bisulfite sequencing to determine the methyla tion status of the ABL1 promoter in 18 Ph-positive ALL samples. We report h ere that gene-specific ABL1 promoter methylation is associated mainly with the P210 form of BCR-ABL and not the P190 form. While six out of the seven P210-positive ALL samples had ABL1 promoter methylation, none of the 11 P19 0-positive ALL samples demonstrated ABL1 promoter methylation. In addition, we estimated the extent and relative abundance of ABL1 promoter methylatio n in several Ph-positive ALL samples and compared it to the methylation pat tern in chronic, accelerated and blastic crisis phases of CML. We put forth a model that correlates the different types of leukemias with the differen t levels of ABL1 promoter methylation.