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

Authors: Wöhrle, 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 
Citation: Wöhrle FU, etal., Leukemia. 2013 Jan;27(1):118-29. doi: 10.1038/leu.2012.222. Epub 2012 Aug 3.
Pubmed: (View Article at PubMed) PMID:22858987
DOI: Full-text: DOI:10.1038/leu.2012.222

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), whereas 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 PI3K 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.

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CRRD Object Information
CRRD ID: 13699433
Created: 2018-07-13
Species: All species
Last Modified: 2018-07-13
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.