title: Targeting of the N-terminal coiled coil oligomerization interface by a helix-2 peptide inhibits unmutated and imatinib-resistant BCR/ABL.
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.
authors: Med. Klinik II/Abt. Hämatologie, Johann Wolfgang Goethe-Universität, 60590 Frankfurt, Germany. beissert@em.uni-frankfurt.de
authors: Tim
authors: T
authors: Beissert
authors: Alena
authors: A
authors: Hundertmark
authors: Velina
authors: V
authors: Kaburova
authors: Lorena
authors: L
authors: Travaglini
authors: Afsar A
authors: AA
authors: Mian
authors: Clara
authors: C
authors: Nervi
authors: Martin
authors: M
authors: Ruthardt
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D001549:Benzamides; D001704:Biopolymers / Q000737:chemistry*; D002460:Cell Line; D017931:DNA Primers; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D001704:Biopolymers; D017931:DNA Primers; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl