Targeting of the N-terminal coiled coil oligomerization interface by a helix-2 peptide inhibits unmutated and imatinib-resistant BCR/ABL
✍ Scribed by Tim Beissert; Alena Hundertmark; Velina Kaburova; Lorena Travaglini; Afsar A. Mian; Clara Nervi; Martin Ruthardt
- Book ID
- 102863645
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- French
- Weight
- 1005 KB
- Volume
- 122
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Abstract
The BCR/ABL oncogene is responsible for the phenotype of Philadelphia chromosome‐positive (Ph+) leukemia. BCR/ABL exhibits an aberrant ABL‐tyrosine kinase activity. The treatment of advanced Ph+ leukemia with selective ABL‐kinase inhibitors such as Imatinib, Nilotinib and Dasatinib is initially effective but rapidly followed by resistance mainly because of specific mutations in BCR/ABL. Tetramerization of ABL through the N‐terminal coiled‐coil region (CC) of BCR is essential for the ABL‐kinase activation. Targeting the CC‐domain forces BCR/ABL into a monomeric conformation reduces its kinase activity and increases the sensitivity for Imatinib. We show that (i) targeting the tetramerization by a peptide representing the Helix‐2 of the CC efficiently reduced the autophosphorylation of both unmutated and mutated BCR/ABL; (ii) Helix‐2 inhibited the transformation potential of BCR/ABL independently of the presence of mutations; and (iii) Helix‐2 efficiently cooperated with Imatinib as revealed by their effects on the transformation potential and the factor‐independence related to BCR/ABL with the exception of mutant T315I. These findings support earlier observations that BCR/ABL harboring the T315I mutation have a transformation potential that is at least partially independent of its kinase activity. These data provide evidence that the inhibition of tetramerization inhibits BCR/ABL‐mediated transformation and can contribute to overcome Imatinib‐resistance. © 2008 Wiley‐Liss, Inc.