دورية أكاديمية
p185BCR/ABL has a lower sensitivity than p210BCR/ABL to the allosteric inhibitor GNF-2 in Philadelphia chromosome-positive acute lymphatic leukemia
| العنوان: | p185BCR/ABL has a lower sensitivity than p210BCR/ABL to the allosteric inhibitor GNF-2 in Philadelphia chromosome-positive acute lymphatic leukemia |
|---|---|
| المؤلفون: | Afsar A. Mian, Anna Metodieva, Yousef Najajreh, Oliver G. Ottmann, Jamal Mahajna, Martin Ruthardt |
| المصدر: | Haematologica, Vol 97, Iss 2 (2012) |
| بيانات النشر: | Ferrata Storti Foundation, 2012. |
| سنة النشر: | 2012 |
| المجموعة: | LCC:Diseases of the blood and blood-forming organs |
| مصطلحات موضوعية: | Diseases of the blood and blood-forming organs, RC633-647.5 |
| الوصف: | Background The t(9;22) translocation leads to the formation of the chimeric breakpoint cluster region/c-abl oncogene 1 (BCR/ABL) fusion gene on der22, the Philadelphia chromosome. The p185BCR/ABL or the p210BCR/ABL fusion proteins are encoded as a result of the translocation, depending on whether a “minor” or “major” breakpoint occurs, respectively. Both p185BCR/ABL and p210BCR/ABL exhibit constitutively activated ABL kinase activity. Through fusion to BCR the ABL kinase in p185BCR/ABL and p210BCR/ABL “escapes” the auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. A novel class of compounds including GNF-2 restores allosteric inhibition of the kinase activity and the transformation potential of BCR/ABL. Here we investigated whether there are differences between p185BCR/ABL and p210BCR/ABL regarding their sensitivity towards allosteric inhibition by GNF-2 in models of Philadelphia chromosome-positive acute lymphatic leukemia.Design and Methods We investigated the anti-proliferative activity of GNF-2 in different Philadelphia chromosome-positive acute lymphatic leukemia models, such as cell lines, patient-derived long-term cultures and factor-dependent lymphatic Ba/F3 cells expressing either p185BCR/ABL or p210BCR/ABL and their resistance mutants.Results The inhibitory effects of GNF-2 differed constantly between p185BCR/ABL and p210BCR/ABL expressing cells. In all three Philadelphia chromosome-positive acute lymphatic leukemia models, p210BCR/ABL-transformed cells were more sensitive to GNF-2 than were p185BCR/ABL-positive cells. Similar results were obtained for p185BCR/ABL and the p210BCR/ABL harboring resistance mutations.Conclusions Our data provide the first evidence of a differential response of p185BCR/ABL- and p210BCR/ABL- transformed cells to allosteric inhibition by GNF-2, which is of importance for the treatment of patients with Philadelphia chromosome-positive acute lymphatic leukemia. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 0390-6078 1592-8721 |
| Relation: | https://haematologica.org/article/view/6215; https://doaj.org/toc/0390-6078; https://doaj.org/toc/1592-8721 |
| DOI: | 10.3324/haematol.2011.047191 |
| URL الوصول: | https://doaj.org/article/47d214ff24424bc4ad362d332d0769ec |
| رقم الأكسشن: | edsdoj.47d214ff24424bc4ad362d332d0769ec |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 03906078 15928721 |
|---|---|
| DOI: | 10.3324/haematol.2011.047191 |