ArticleLeukemia2013
Gab2 signaling in chronic myeloid leukemia cells confers resistance to multiple Bcr-Abl inhibitors.
Article in Leukemia, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 52 citations in OpenAlex.
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- Mast cell deficiency prevents BCR::ABL1 induced splenomegaly and cytokine elevation in a CML mouse model.Leukemia · 2023Article
- Activation of ERK1/2 by MOS and TPL2 leads to dasatinib resistance in chronic myeloid leukaemia cells.Cell proliferation · 2023Article
- Therapeutic targeting of LCK tyrosine kinase and mTOR signaling in T-cell acute lymphoblastic leukemia.Blood · 2022Article
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- Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia-From Molecular Mechanisms to Clinical Relevance.Cancers · 2021Review
- Current Views on the Interplay between Tyrosine Kinases and Phosphatases in Chronic Myeloid Leukemia.Cancers · 2021Review
- 14-3-3 Proteins: Novel Pharmacological Targets in Neurodegenerative Diseases.Trends in pharmacological sciences · 2021Review
- SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia.Leukemia · 2020Article
- Article
- [Protein-dysregulation in human and murine myeloproliferative neoplasms].Der Pathologe · 2018Review
- BRAF inhibition upregulates a variety of receptor tyrosine kinases and their downstream effector Gab2 in colorectal cancer cell lines.Oncogene · 2018Article
- Epigenetic regulation of HOTAIR in advanced chronic myeloid leukemia.Cancer management and research · 2018Article
- The Atypical Kinase RIOK1 Promotes Tumor Growth and Invasive Behavior.EBioMedicine · 2017Article
- Elevated Gab2 induces tumor growth and angiogenesis in colorectal cancer through upregulating VEGF levels.Journal of experimental & clinical cancer research : CR · 2017Article
- Efficacy of the dual PI3K and mTOR inhibitor NVP-BEZ235 in combination with imatinib mesylate against chronic myelogenous leukemia cell lines.Drug design, development and therapy · 2017Article
- Gab2 is essential for Bcr-Abl-mediated leukemic transformation and hydronephrosis in a chronic myeloid leukemia mouse model.Leukemia · 2016Article
Corrections and comments
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Authors and funding
15 authors at 6 institutions in 5 countries.
Funding
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), 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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.