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

Abstract

In human Ph-positive leukemia there is a clear association of different forms of the BCR-ABL oncogene with distinct types of leukemia. The P190 form of BCR-ABL is rarely observed in chronic myeloid leukemia (CML) but is present in 50% of Phpositive acute lymphoblastic leukemia (ALL). In contrast, the P210 form is observed both in CML and 50% of Ph-positive ALL. Methylation of the proximal promoter of the ABL1 gene has been shown to be a nearly universal event associated with clinical progression of CML. This raises the question of whether methylation of the ABL1 promoter is an epigenetic modification also associated with Ph-positive ALL. To study this issue, we used methylation-specific PCR and bisulfite sequencing to determine the methylation status of the ABL1 promoter in 18 Ph-positive ALL samples. We report here 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 P190-positive ALL samples demonstrated ABL1 promoter methylation. In addition, we estimated the extent and relative abundance of ABL1 promoter methylation in several Ph-positive ALL samples and compared it to the methylation pattern in chronic, accelerated and blastic crisis phases of CML. We put forth a model that correlates the different types of leukemias with the different levels of ABL1 promoter methylation. Leukemia (2001) 15, 575-582.

Role of promoter methylation in regulation of the mammalian heparanase gene

“…The bisulfite reagent was prepared as follows: 1.9 g of sodium bisulfite (Sigma Israel, Rehovot) were slowly dissolved in sterile water on a gentle rocker. The total volume was 4 ml, containing 0.7 ml 2 N NaOH and 0.5 ml of a saturated solution of hydroquinone (Sigma) in water (Shteper et al, 2001).…”

Epigenetics of Acute Lymphocytic Leukemia

“…Expression of CD10 was inversely associated with methylation of CD10. At the genetic level, methylation of c-ABL was only observed in patients with Philadelphia chromosome alterations (Ph), and only in those patients with the p210 isoform, a reproducible result 31 . In the exploratory study, an association was observed between methylation and worse prognosis (for p73 and p15).…”

p210 BCR-ABL1 positive pediatric B-lineage acute lymphoblastic leukemia presenting with hypercalcemia

“…[3,4] Among adult patients with Ph þ ALL, both p190 and p210 are found with equal frequency of 50%; while p190 protein has been described in 90% of pediatric Ph þ ALL. [2,[5][6][7] However, there are no significant hematological or prognostic differences between p210 and p190 expressing Ph þ ALL. [6,7] Pediatric Ph þ ALL usually presents during later childhood with high leukocyte counts and frequent central nervous system involvement.…”

“…[2,[5][6][7] However, there are no significant hematological or prognostic differences between p210 and p190 expressing Ph þ ALL. [6,7] Pediatric Ph þ ALL usually presents during later childhood with high leukocyte counts and frequent central nervous system involvement. [2,8] Though it is difficult to delineate between de novo BCR-ABL1 positive ALL and blast crisis of chronic myelogenous leukemia (CML), age at diagnosis, absence of splenomegaly and basophilia favor de novo BCR-ABL1 positive ALL.…”