Journal
LEUKEMIA
Volume 27, Issue 1, Pages 118-129Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2012.222
Keywords
Bcr-Abl; Gab2; TKI resistance; imatinib; rapamycin; 14-3-3
Categories
Funding
- German Research Foundation (DFG) through the Emmy-Noether-Program [BR3662/1-1]
- EXC 294 BIOSS
- Excellence Initiative of the DFG [GSC-4]
- DFG [ZE 872/1-1, ZE 872/2-1, Pa 611/5-1, Pa 611/6-1]
- DFG funded Collaborative Research Center [850]
- NIH [PO1 CA108671]
- National Health and Medical Research Council of Australia
- Austrian Academy of Sciences through an APART fellowship
- University of Freiburg
- NATIONAL CANCER INSTITUTE [P01CA108671] Funding Source: NIH RePORTER
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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. Leukemia (2013) 27, 118-129; doi:10.1038/leu.2012.222
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