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. 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. 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. 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.
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 . 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 . 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 . 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 .
What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?
What tyrosine kinase , involved in a Philadelphia- chromosome positive chronic myelogenous leukemia , is the target of Imatinib ( Gleevec ) ?
BCR-ABL
BCR-ABL