RESEARCH ARTICLE
Targeting the Oligomerization of BCR/ABL by Membrane Permeable Competitive Peptides Inhibits the Proliferation of Philadelphia Chromosome Positive Leukemic Cells
Afsar Ali Mian1, Marion Schull1, Claudia Oancea1, Yousef Najajreh2, Jamal Mahajna2, Amiram Goldblum3, Oliver Gerhard Ottmann4, Tim Beissert1, *, Martin Ruthardt1, *
Article Information
Identifiers and Pagination:
Year: 2011Volume: 5
First Page: 21
Last Page: 27
Publisher Id: TOHJ-5-21
DOI: 10.2174/1874276901105010021
Article History:
Received Date: 08/08/2011Revision Received Date: 16/09/2011
Acceptance Date: 19/09/2011
Electronic publication date: 30/12/2011
Collection year: 2011
open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
The BCR/ABL fusion protein is the hallmark of Philadelphia Chromosome positive (Ph+) leukemia. The constitutive activation of the ABL-kinase in BCR/ABL cells induces the leukemic phenotype. Targeted inhibition of BCR/ABL by small molecule inhibitors reverses the transformation potential of BCR/ABL. Recently, we definitively proved that targeting the tetramerization of BCR/ABL mediated by the N-terminal coiled-coil domain (CC) using competitive peptides, representing the helix-2 of the CC, represents a valid therapeutic approach for treating Ph+ leukemia. To further develop competitive peptides for targeting BCR/ABL, we created a membrane permeable helix-2 peptide (MPH-2) by fusing the helix-2 peptide with a peptide transduction tag. In this study, we report that the MPH-2: (i) interacted with BCR/ABL in vivo; (ii) efficiently inhibited the autophosphorylation of BCR/ABL; (iii) suppressed the growth and viability of Ph+ leukemic cells; and (iv) was efficiently transduced into mononuclear cells (MNC) in an in vivo mouse model.
This study provides the first evidence that an efficient peptide transduction system facilitates the employment of competitive peptides to target the oligomerization interface of BCR/ABL in vivo.
