Targeting the oligomerization of BCR/ABL by membrane permeable competitive peptides inhibits the proliferation of Philadelphia Chromosome positive leukemic cells
- 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.
Author: | Afsar Ali MianORCiDGND, Marion Schüll, Claudia Oancea, Yousef Najajreh, Jamal Mahajna, Amiram Goldblum, Oliver G. OttmannORCiDGND, Tim Beißert, Martin RuthardtORCiD |
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URN: | urn:nbn:de:hebis:30:3-288599 |
DOI: | https://doi.org/10.2174/1874276901105010021 |
ISSN: | 1874-2769 |
Parent Title (English): | The open hematology journal |
Publisher: | Bentham Open |
Place of publication: | Sharjah |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2013/02/12 |
Year of first Publication: | 2011 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2013/02/12 |
Tag: | BCR/ABL; Philadelphia Chromosome-positive leukemia; competitive peptide; molecular targeting; oligomerization |
Volume: | 5 |
Page Number: | 7 |
First Page: | 21 |
Last Page: | 27 |
Note: | © Mian et al.; Licensee Bentham Open. This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited. |
HeBIS-PPN: | 331480093 |
Institutes: | Medizin / Medizin |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Sammlungen: | Universitätspublikationen |
Licence (German): | Creative Commons - Namensnennung-Nicht kommerziell 3.0 |