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BCR: a new target in resistance mediated by BCR/ABL-315I?

Haberbosch, Isabella, Rafiei, Anahita, Oancea, Claudia, Ottmann, Oliver, Ruthardt, Martin and Mian, Afsar 2016. BCR: a new target in resistance mediated by BCR/ABL-315I? Genes & Cancer 7 (1-2) , pp. 36-46.

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Abstract

Targeting BCR/ABL with Tyrosine kinase inhibitors (TKIs) is a proven concept for the treatment of Philadelphia chromosome-positive (Ph+) leukemias. The most important mechanism of resistance against TKIs is the selection of leukemic clones driven by BCR/ABL harboring point mutations. 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 for the effects of T315I on BCR/ABL mutants lacking functional domains indispensable for the oncogenic activity of BCR/ABL. As models 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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: SAGE Publications
ISSN: 1947-6019
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 20 January 2016
Last Modified: 26 Dec 2017 20:21
URI: http://orca-mwe.cf.ac.uk/id/eprint/85933

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