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dc.contributor.authorMian, Afsar Ali
dc.contributor.authorMetodieva, Anna
dc.contributor.authorBadura, Susanne
dc.contributor.authorKhateb, Mamduh
dc.contributor.authorNajajreh, Yousef
dc.contributor.authorOttmann, Oliver Gerhard
dc.contributor.authorMahajna, Jamal
dc.contributor.authorRuthardt, Martin
dc.date.accessioned2018-09-05T08:29:16Z
dc.date.available2018-09-05T08:29:16Z
dc.date.issued2012-09-17
dc.identifier.issn1471-2407
dc.identifier.urihttps://dspace.alquds.edu/handle/20.500.12213/839
dc.description.abstractBackground: 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.en_US
dc.description.sponsorshipThis study was supported by a grant from the German Research Foundation (DFG) to MR, JM and YN (DFG-RU 728/3-2).en_US
dc.language.isoen_USen_US
dc.publisherBioMed Centralen_US
dc.subjectPhiladelphia chromosomeen_US
dc.subjectBCR/ABLen_US
dc.subjectgatekeeper” mutation T315Ien_US
dc.subjectAllosteric inhibitionen_US
dc.subjectAbl kinase inhibitorsen_US
dc.subjectMolecular therapyen_US
dc.titleAllosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABLand BCR-ABL-T315Ien_US
dc.typeArticleen_US


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