p185^BCR/ABL has a lower sensitivity than p210^BCR/ABL to the allosteric inhibitor GNF-2 in Philadelphia chromosome-positive acute lymphatic leukemia

Background: The t(9;22) translocation leads to the formation of the chimeric breakpoint cluster region/c-abl oncogene 1 (BCR/ABL) fusion gene on der22, the Philadelphia chromosome. The p185^BCR/ABL or the p210^BCR/ABL fusion proteins are encoded as a result of the translocation, depending on whether a "minor" or "major" breakpoint occurs, respectively. Both p185^BCR/ABL and p210^BCR/ABL exhibit constitutively activated ABL kinase activity. Through fusion to BCR the ABL kinase in p185^BCR/ABL and p210^BCR/ABL "escapes" the auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. A novel class of compounds including GNF-2 restores allosteric inhibition of the kinase activity and the transformation potential of BCR/ABL. Here we investigated whether there are differences between p185^BCR/ABL and p210^BCR/ABL regarding their sensitivity towards allosteric inhibition by GNF-2 in models of Philadelphia chromosome-positive acute lymphatic leukemia. Design and Methods: We investigated the anti-proliferative activity of GNF-2 in different Philadelphia chromosome-positive acute lymphatic leukemia models, such as cell lines, patient-derived long-term cultures and factor-dependent lymphatic Ba/F3 cells expressing either p185^BCR/ABL or p210^BCR/ABL and their resistance mutants. Results: The inhibitory effects of GNF-2 differed constantly between p185^BCR/ABL and p210^BCR/ABL expressing cells. In all three Philadelphia chromosome-positive acute lymphatic leukemia models, p210^BCR/ABL-transformed cells were more sensitive to GNF-2 than were p185BCR/ABL-positive cells. Similar results were obtained for p185^BCR/ABL and the p210^BCR/ABL harboring resistance mutations. Conclusions: Our data provide the first evidence of a differential response of p185^BCR/ABL- and p210^BCR/ABL- transformed cells to allosteric inhibition by GNF-2, which is of importance for the treatment of patients with Philadelphia chromosome-positive acute lymphatic leukemia.