BACKGROUND: Chronic myelogenous leukemia (CML) and Philadelphia 
chromosome-positive (Ph+) acute lymphatic leukemia (Ph + ALL) are caused by the 
t(9;22), which fuses BCR to ABL resulting in deregulated ABL-tyrosine kinase 
activity. The constitutively activated BCR/ABL-kinase "escapes" the 
auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. The 
ABL-kinase inhibitors (AKIs) Imatinib, Nilotinib or Dasatinib, which target the 
ATP-binding site, are effective in Ph + leukemia. Another molecular therapy 
approach targeting BCR/ABL restores allosteric inhibition. Given the fact that 
all AKIs fail to inhibit BCR/ABL harboring the 'gatekeeper' mutation T315I, we 
investigated the effects of AKIs in combination with the allosteric inhibitor 
GNF2 in Ph + leukemia.
METHODS: The efficacy of this approach on the leukemogenic potential of BCR/ABL 
was studied in Ba/F3 cells, primary murine bone marrow cells, and untransformed 
Rat-1 fibroblasts expressing BCR/ABL or BCR/ABL-T315I as well as in 
patient-derived long-term cultures (PDLTC) from Ph + ALL-patients.
RESULTS: Here, we show that GNF-2 increased the effects of AKIs on unmutated 
BCR/ABL. Interestingly, the combination of Dasatinib and GNF-2 overcame 
resistance of BCR/ABL-T315I in all models used in a synergistic manner.
CONCLUSIONS: Our observations establish a new approach for the molecular 
targeting of BCR/ABL and its resistant mutants using a combination of AKIs and 
allosteric inhibitors.