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Targeting of the N‐terminal coiled coil oligomerization interface by a helix‐2 peptide inhibits unmutated and imatinib‐resistant BCR/ABL
Author(s) -
Beissert Tim,
Hundertmark Alena,
Kaburova Velina,
Travaglini Lorena,
Mian Afsar A.,
Nervi Clara,
Ruthardt Martin
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23467
Subject(s) - autophosphorylation , abl , dasatinib , nilotinib , imatinib mesylate , cancer research , tyrosine kinase , imatinib , philadelphia chromosome , chemistry , protein kinase domain , breakpoint cluster region , kinase , biology , mutant , microbiology and biotechnology , protein kinase a , biochemistry , signal transduction , chromosomal translocation , receptor , myeloid leukemia , gene
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.