p185BCR/ABL has a lower sensitivity than p210BCR/ABL to the allosteric inhibitor GNF-2 in Philadelphia chromosome-positive acute lymphatic leukemia
Date
2012-02-03
Authors
Mian, Afsar A.
Metodieva, Anna
Najajreh, Yousef
Ottmann, Oliver G.
Mahajna, Jamal
Ruthardt, Martin
Journal Title
Journal ISSN
Volume Title
Publisher
Ferrata Storti Foundation (Italy)
Abstract
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 chromosomepositive
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.
Description
Keywords
Philadelphia chromosome , BCR/ABL , allosteric inhibition , acute lymphatic leukemia , molecular therapy
Citation
Mian AA, Metodieva A, Najajreh Y, Ottmann OG, Mahajna J, and Ruthardt M. p185BCR/ABL has a lower sensitivity than p210BCR/ABL to the allosteric inhibitor GNF-2 in Philadelphia chromosome-positive acute lymphatic leukemia. Haematologica 2012;97(2):251-257. doi:10.3324/haematol.2011.047191