title: BCR: a new target in resistance mediated by BCR/ABL-315I?
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.
authors.affiliation: Department of Hematology, Goethe University, Frankfurt, Germany.
authors.forename: Isabella
authors.initials: I
authors.lastname: Haberbosch
authors.affiliation: Department of Hematology, University of Zurich, Zurich, Switzerland.
authors.forename: Anahita
authors.initials: A
authors.lastname: Rafiei
authors.affiliation: Deparment of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Claudia
authors.initials: C
authors.lastname: Oancea
authors.affiliation: Deparment of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom; Cardiff Experimental Cancer Medicine Centre (ECMC), Cardiff, United Kingdom.
authors.forename: Gerhart Oliver
authors.initials: GO
authors.lastname: Ottmann
authors.affiliation: Deparment of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Ruthardt
authors.affiliation: Deparment of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Afsar Ali
authors.initials: AA
authors.lastname: Mian
keywords: BCR/ABL; Philadelphia chromosome-positive leukemia; endogenous BCR; resistant mutation T315I