ArticleJournal of experimental & clinical cancer research : CR2020
De-regulated STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis suppresses CML cell apoptosis and contributes to Imatinib resistance.
Article in Journal of experimental & clinical cancer research : CR, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 39 citations in OpenAlex.
- Targeting STAT5A via CRISPR/Cas9 restores TKI sensitivity in resistant chronic myeloid leukemia cells.Medical oncology (Northwood, London, England) · 2026Article
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- A selenium-containing selective estrogen receptor modulator to overcome drug resistance of chronic myeloid leukemia.Apoptosis : an international journal on programmed cell death · 2026Article
- Machine learning-based prediction reveals kinase MAP4K4 regulates neutrophil differentiation through phosphorylating apoptosis-related proteins.PLoS computational biology · 2025Article
- Targeting regulated cell death: Apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis in anticancer immunity.Journal of translational internal medicine · 2025Article
- Impact of non-coding RNAs on resistance to imatinib in chronic myelogenous leukemia.Leukemia research reports · 2025Review
- Exploiting the potential of the ubiquitin-proteasome system in overcoming tyrosine kinase inhibitor resistance in chronic myeloid leukemia.Genes & diseases · 2024Review
- Alternation of gene expression in brain-derived exosomes after cerebral ischemic preconditioning in mice.Heliyon · 2024Article
- Drug resistance mechanisms and treatment strategies mediated by Ubiquitin-Specific Proteases (USPs) in cancers: new directions and therapeutic options.Molecular cancer · 2024Review
- Non-coding RNAs in leukemia drug resistance: new perspectives on molecular mechanisms and signaling pathways.Annals of hematology · 2024Review
- TRIM21/USP15 balances ACSL4 stability and the imatinib resistance of gastrointestinal stromal tumors.British journal of cancer · 2024Article
- Article
- Identification of apoptosis-related key genes and the associated regulation mechanism in thoracic aortic aneurysm.BMC cardiovascular disorders · 2023Article
- Protein degradation: expanding the toolbox to restrain cancer drug resistance.Journal of hematology & oncology · 2023Review
- Article
- SALIS transcriptionally represses IGFBP3/Caspase-7-mediated apoptosis by associating with STAT5A to promote hepatocellular carcinoma.Cell death & disease · 2022Article
- Circulating microRNAs Suggest Networks Associated with Biological Functions in Aggressive Refractory Type 2 Celiac Disease.Biomedicines · 2022Article
- The microRNA-202 as a Diagnostic Biomarker and a Potential Tumor Suppressor.International journal of molecular sciences · 2022Review
- Restoration of miR-23a expression by chidamide sensitizes CML cells to imatinib treatment with concomitant downregulation of CRYAB.Bioengineered · 2022Article
- USP15 in Cancer and Other Diseases: From Diverse Functionsto Therapeutic Targets.Biomedicines · 2022Review
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundSTAT5 plays an important role in the transformation of hematopoietic cells by BCR-ABL. However, the downstream target genes activated by STAT5 in chronic myeloid leukemia (CML) cells remain largely unclear. Here, we investigated the mechanistic functional relationship between STAT5A-regulated microRNA and CML cell apoptosis.
methodsThe expression of USP15, Caspase-6, STAT5A-regulated miR-202-5p and STAT5A was detected by qRT-PCR and Western blotting in CML cell lines and PBMCs of CML patients. Cell apoptosis was evaluated by flow cytometry. Both gain- and loss-of-function experiments were used to investigate the roles of USP15, miR-202-5p and STAT5A in CML. Luciferase reporter assay detected the effect of miR-202-5p on USP15 expression. Xenograft animal model was used to test the effect of anti-miR-202-5p and pimozide on K562 cell xenograft growth.
resultsUSP15 expression was significantly downregulated in CML cell lines and PBMCs of CML patients. Depletion of USP15 increased, whereas overexpression of USP15 reduced the resistance of CML cells to Imatinib. Further, decreased deubiquitinating activity of USP15 by USP15 downregulation led to reduced caspase-6 level, thus attenuating CML cell apoptosis. Mechanistically, miR-202-5p was upregulated in K562G cells and negatively regulated USP15 expression by directly targeting USP15 3'-UTR. Correspondingly, upregulation of miR-202-5p enhanced the resistance of CML cells to Imatinib by inhibiting cell apoptosis. Importantly, STAT5A was upregulated in CML cells and directly activated miR-202-5p transcription by binding to the pre-miR-202 promoter. Pimozide induced CML cell apoptosis and significantly reduced K562 cell xenograft growth in vivo by blocking STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis.
conclusionswe provide the first evidence that de-regulated STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis suppresses the apoptosis of CML cells, targeting this pathway might be a promising therapeutic approach for the treatment of CML.
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