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Gab2 signaling in chronic myeloid leukemia cells confers resistance to multiple Bcr-Abl inhibitors

Abstract

Grb2-associated binder 2 (Gab2) serves as a critical amplifier in the signaling network of Bcr-Abl, the driver of chronic myeloid leukemia (CML). Despite the success of tyrosine kinase inhibitors (TKIs) in CML treatment, TKI-resistance, caused by mutations in Bcr-Abl or aberrant activity of its network partners, remains a clinical problem. Using inducible expression and knockdown systems, we analyzed the role of Gab2 in Bcr-Abl signaling in human CML cells, especially with respect to TKI-sensitivity. We show for the first time that Gab2 signaling protects CML cells from various Bcr-Abl inhibitors (imatinib, nilotinib, dasatinib and GNF-2), while Gab2 knockdown or haploinsufficiency leads to increased TKI-sensitivity. We dissected the underlying molecular mechanism using various Gab2 mutants and kinase inhibitors and identified the Shp2/Ras/ERK and the PI3K/AKT/mTOR axes as the two critical signaling pathways. Gab2-mediated TKI-resistance was associated with persistent phosphorylation of Gab2 Y452, a PI3 K recruitment site, and consistent with this finding, the protective effect of Gab2 was completely abolished by the combination of dasatinib with the dual PI3K/mTOR inhibitor NVP-BEZ235. The identification of Gab2 as a novel modulator of TKI-sensitivity in CML suggests that Gab2 could be exploited as a biomarker and therapeutic target in TKI-resistant disease.Leukemia accepted article preview online, 3 August 2012;doi:10.1038/leu.2012.222.

Type Journal
Authors Wohrle, F. U.; Halbach, S.; Aumann, K.; Schwemmers, S.; Braun, S.; Auberger, P.; Schramek, D.; Penninger, J. M.; Lassmann, S.; Werner, M.; Waller, C. F.; Pahl, H. L.; Zeiser, R.; Daly, R. J.; Brummer, T.;
Publisher Name BLOOD
Published Date 2013-01-15 00:00:00
Published Volume 27
Published Issue 1
Published Pages 118-29
URL http://www.ncbi.nlm.nih.gov/pubmed/22858987
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?11132_12191/12_Wohrle_Leukemia_.pdf