ArticleOncotarget2015
FLT3-ITD confers resistance to the PI3K/Akt pathway inhibitors by protecting the mTOR/4EBP1/Mcl-1 pathway through STAT5 activation in acute myeloid leukemia.
Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 64 citations in OpenAlex.
- Venetoclax for elderly patients with acute myeloid leukaemia unfit for intensive chemotherapy: Prospects, resistance mechanisms and management strategies.Clinical and translational medicine · 2026Review
- Ribosome biogenesis and selective translational control as oncogenic vulnerabilities in hematologic malignancies.Molecular cancer · 2026Review
- Autophagy inhibition potentiates the antileukemic effect of FLT3 inhibitors and overcomes resistance in FLT3-ITD acute myeloid leukemia.Cell death discovery · 2026Article
- Selective EV Protein Sorting and Pathway Perturbation in AML Upon Synergistic FLT3 and Hedgehog Pathway Inhibition.Journal of extracellular vesicles · 2025Article
- Effects of venetoclax, a BCL2 inhibitor, in systemic chronic active Epstein-Barr virus disease.Scientific reports · 2025Article
- Discovery of novel and highly potent small molecule inhibitors targeting FLT3-ITD for the treatment of acute myeloid leukemia using structure-based virtual screening and biological evaluation.Frontiers in pharmacology · 2025Article
- Targeting USP14/UCHL5: A Breakthrough Approach to Overcoming Treatment-Resistant FLT3-ITD-Positive AML.International journal of molecular sciences · 2024Article
- Article
- Combination of an Oxindole Derivative with (-)-β-Elemene Alters Cell Death Pathways in FLT3/ITDMolecules (Basel, Switzerland) · 2023Article
- METTL3 affects FLT3-ITD+ acute myeloid leukemia by mediating autophagy by regulating PSMA3-AS1 stability.Cell cycle (Georgetown, Tex.) · 2023Article
- Pimozide and Imipramine Blue Exploit Mitochondrial Vulnerabilities and Reactive Oxygen Species to Cooperatively Target High Risk Acute Myeloid Leukemia.Antioxidants (Basel, Switzerland) · 2021Article
- CD52 is a novel target for the treatment of FLT3-ITD-mutated myeloid leukemia.Cell death discovery · 2021Article
- PP2A-activating Drugs Enhance FLT3 Inhibitor Efficacy through AKT Inhibition-Dependent GSK-3β-Mediated c-Myc and Pim-1 Proteasomal Degradation.Molecular cancer therapeutics · 2021Article
- Case Report: A Novel Activating FLT3 Mutation in Acute Myeloid Leukemia.Frontiers in oncology · 2021Article
- Repurposing antipsychotics of the diphenylbutylpiperidine class for cancer therapy.Seminars in cancer biology · 2021Review
- Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence.Journal of clinical medicine · 2020Review
- Involvement of STAT5 in Oncogenesis.Biomedicines · 2020Review
- Combinatorial Inhibition of Focal Adhesion Kinase and BCL-2 Enhances Antileukemia Activity of Venetoclax in Acute Myeloid Leukemia.Molecular cancer therapeutics · 2020Article
- Article
- Defects in mTORC1 Network and mTORC1-STAT3 Pathway Crosstalk Contributes to Non-inflammatory Hepatocellular Carcinoma.Frontiers in cell and developmental biology · 2020Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
FLT3-ITD and FLT3-TKD are the most frequent tyrosine kinase mutations in acute myeloid leukemia (AML), with the former associated with poor prognosis. Here, we show that the PI3K inhibitor GDC-0941 or the Akt inhibitor MK-2206 induced apoptosis through the mitochondria-mediated intrinsic pathway more efficiently in hematopoietic 32D cells driven by FLT3-TKD (32D/TKD) than FLT3-ITD (32D/ITD), which robustly activated STAT5. The resistance to GDC-0941 and MK-2206 was gained by expression of the constitutively activated STAT5 mutant STAT5A1*6 in 32D/TKD cells, while it was abrogated by the STAT5 inhibitor pimozide in 32D/ITD cells or FLT3-ITD-expressing human leukemic MV4-11 cells. GDC-0941 or MK-2206 induced dephosphorylation of 4EBP1 more conspicuously in 32D/TKD than in 32D/ITD, which was prevented or augmented by STAT5A1*6 or pimozide, respectively, and correlated with downregulation of the eIF4E/eIF4G complex formation and Mcl-1 expression. Furthermore, exogenous expression of Mcl-1 endowed resistance to GDC-0941 and MK-2206 on 32D/TKD cells. Finally, it was confirmed in primary AML cells with FLT3-ITD that pimozide enhanced 4EBP1 dephosphorylation and Mcl-1 downregulation to augment cytotoxicity of GDC-0941. These data suggest that the robust STAT5 activation by FLT3-ITD protects cells treated with the PI3K/Akt pathway inhibitors from apoptosis by maintaining Mcl-1 expression through the mTORC1/4EBP1/eIF4E pathway.
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