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Molecular Targets for Therapy

Oligomerization inhibition, combined with allosteric inhibition, abrogates the transformation potential of T315I-positive BCR/ABL


The t(9;22) translocation leads to the formation of the chimeric bcr/abl fusion gene, which encodes the BCR/ABL fusion protein. In contrast to its physiological counterpart c-ABL, the BCR/ABL kinase is constitutively activated, inducing the leukemic phenotype. The N-terminus of c-ABL (Cap region) contributes to the regulation of its kinase function. It is myristoylated, and the myristate residue binds to a hydrophobic pocket in the kinase domain known as the myristoyl-binding pocket in a process called ‘capping’, which results in an auto-inhibited conformation. Because the cap region is replaced by the N-terminus of BCR, the BCR/ABL ‘escapes’ this auto-inhibition. Allosteric inhibition by myristate ‘mimics’, such as GNF-2, is able to inhibit unmutated BCR/ABL, but not the BCR/ABL that harbors the ‘gatekeeper’ mutation T315I. In this study, we analyzed the possibility of increasing the efficacy of allosteric inhibition by blocking BCR/ABL oligomerization. We showed that inhibition of oligomerization was able to not only increase the efficacy of GNF-2 on unmutated BCR/ABL, but also overcome the resistance of BCR/ABL-T315I to allosteric inhibition. These results strongly suggest that the response to allosteric inhibition by GNF-2 is inversely related to the degree of oligomerization of BCR/ABL. In summary, our observations establish a new approach for the molecular targeting of BCR/ABL and its resistant mutants represented by the combination of oligomerization and allosteric inhibitors.

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This study was supported by a grant from the Deutsche Forschungsgemeinschaft to MR (DFG-RU 728/3-1). MR is further funded by grants from Deutsche Krebshilfe e.V. (DKH-107063 and DKH-107741), Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLS–R 07/27f) and the Alfred und Angelika Gutermuth Foundation.

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Correspondence to M Ruthardt.

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Mian, A., Oancea, C., Zhao, Z. et al. Oligomerization inhibition, combined with allosteric inhibition, abrogates the transformation potential of T315I-positive BCR/ABL. Leukemia 23, 2242–2247 (2009).

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  • Philadelphia chromosome-positive leukemia
  • imatinib-resistance
  • ‘gatekeeper’ mutation T315I
  • inhibition of oligomerization
  • allosteric inhibition

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