BCR: a new target in resistance mediated by BCR/ABL-315I?
Isabella Haberbosch1, Anahita Rafiei4, Claudia Oancea2, Oliver Gerhart Ottmann2,3, Martin Ruthardt2 and Afsar Ali Mian2
1 Department of Hematology, Goethe University, Frankfurt, Germany
2 Deparment of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom
3 Cardiff Experimental Cancer Medicine Centre (ECMC), Cardiff, United Kingdom
4 Department of Hematology, University of Zurich, Zurich, Switzerland
Correspondence:
Afsar Ali Mian, email:
Correspondence:
Martin Ruthardt, email:
Keywords: Philadelphia chromosome-positive leukemia, BCR/ABL, resistant mutation T315I, endogenous BCR
Received: November 18, 2015 Accepted: January 20, 2016 Published: February 08, 2016
Abstract
Targeting BCR/ABL with Tyrosine kinase inhibitors (TKIs) is a proven concept for the treatment of Philadelphia chromosome-positive (Ph+) leukemias but the “gatekeeper”mutation T315I confers resistance against all approved TKIs, with the only exception of ponatinib, a multi-targeted kinase inhibitor. Besides resistance to TKIs, T315I also confers additional features to the leukemogenic potential of BCR/ABL, involving endogenous BCR. Therefore we studied the role of BCR on BCR/ABL mutants lacking functional domains indispensable for the oncogenic activity of BCR/ABL. We used the factor independent growth of murine myeloid progenitor 32D cells and the transformation of Rat-1 fibroblasts both mediated by BCR/ABL. Here we report that T315I restores the capacity to mediate factor-independent growth and transformation potential of loss-of-function mutants of BCR/ABL. Targeting endogenous Bcr abrogated the capacity of oligomerization deficient mutant of BCR/ABL-T315I to mediate factor independent growth of 32D cells and strongly reduced their transformation potential in Rat-1 cells, as well as led to the up-regulation of mitogen activated protein kinase (MAPK) pathway.
Our data show that the T315I restores the capacity of loss-of-function mutants to transform cells which is dependent on the transphosphorylation of endogenous Bcr, which becomes a putative therapeutic target to overcome resistance by T315I.
