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.