ArticleBMC cancer2015
Enhancing SHP-1 expression with 5-azacytidine may inhibit STAT3 activation and confer sensitivity in lestaurtinib (CEP-701)-resistant FLT3-ITD positive acute myeloid leukemia.
Article in BMC cancer, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05042531 (Clinical Research for Azacitidine Combined With Low-dose Dasatinib in Maintenance Therapy of Acute Myeloid Leukemia), which is not on this map. Cited by 34 papers.
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Clinical Research for Azacitidine Combined With Low-dose Dasatinib in Maintenance Therapy of Acute Myeloid Leukemia
Who cites it
34 citing papers in PubMed.
- Targeting p16Leukemia · 2025Article
- 5-AZA Upregulates SOCS3 and PTPN6/SHP1, Inhibiting STAT3 and Potentiating the Effects of AG490 against Primary Effusion Lymphoma Cells.Current issues in molecular biology · 2024Article
- NRF2 and STAT3: friends or foes in carcinogenesis?Discover oncology · 2023Review
- Synthesis and Biological Evaluation of 3-Amino-4,4-Dimethyl Lithocholic Acid Derivatives as Novel, Selective, and Cellularly Active Allosteric SHP1 Activators.Molecules (Basel, Switzerland) · 2023Article
- The paradigm of drug resistance in cancer: an epigenetic perspective.Bioscience reports · 2022Review
- Thymoquinone Inhibits Growth of Acute Myeloid Leukemia Cells through ReversalPharmaceuticals (Basel, Switzerland) · 2021Article
- STAT3 activation in large granular lymphocyte leukemia is associated with cytokine signaling and DNA hypermethylation.Leukemia · 2021Article
- Genomic Abnormalities as Biomarkers and Therapeutic Targets in Acute Myeloid Leukemia.Cancers · 2021Review
- Thymoquinone Suppresses Cell Proliferation and Enhances Apoptosis of HL60 Leukemia Cells through Re-Expression of JAK/STAT Negative Regulators.Asian Pacific journal of cancer prevention : APJCP · 2021Article
- The role of Src homology region 2 domain-containing phosphatase-1 hypermethylation in the classification of patients with myelodysplastic syndromes and its association with signal transducer and activator of transcription 3 phosphorylation in skm-1 cells.The Journal of international medical research · 2021Article
- Strategy for Leukemia Treatment Targeting SHP-1,2 and SHIP.Frontiers in cell and developmental biology · 2021Review
- High-fat diet intensifies MLL-AF9-induced acute myeloid leukemia through activation of the FLT3 signaling in mouse primitive hematopoietic cells.Scientific reports · 2020Article
- Review
- Advances in targeted therapy for acute myeloid leukemia.Biomarker research · 2020Review
- Understanding the Mechanisms by Which Epigenetic Modifiers Avert Therapy Resistance in Cancer.Frontiers in oncology · 2020Review
- Identification and Validation ofOncoTargets and therapy · 2020Article
- Pharmacologic Therapies to Prevent Relapse of Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation.Frontiers in oncology · 2020Review
- Aberrant DNA Methylation in Acute Myeloid Leukemia and Its Clinical Implications.International journal of molecular sciences · 2019Review
- DNMT3a promotes proliferation by activating the STAT3 signaling pathway and depressing apoptosis in pancreatic cancer.Cancer management and research · 2019Article
- A personalized approach to acute myeloid leukemia therapy: current options.Pharmacogenomics and personalized medicine · 2019Article
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4 authors.
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Abstract
backgroundTumor-suppressor genes are inactivated by methylation in several cancers including acute myeloid leukemia (AML). Src homology-2 (SH2)-containing protein-tyrosine phosphatase 1 (SHP-1) is a negative regulator of the JAK/STAT pathway. Transcriptional silencing of SHP-1 plays a critical role in the development and progression of cancers through STAT3 activation. 5-Azacytidine (5-Aza) is a DNA methyltransferase inhibitor that causes DNA demethylation resulting in re-expression of silenced SHP-1. Lestaurtinib (CEP-701) is a multi-targeted tyrosine kinase inhibitor that potently inhibits FLT3 tyrosine kinase and induces hematological remission in AML patients harboring the internal tandem duplication of the FLT3 gene (FLT3-ITD). However, the majority of patients in clinical trials developed resistance to CEP-701. Therefore, the aim of this study, was to assess the effect of re-expression of SHP-1 on sensitivity to CEP-701 in resistant AML cells.
methodsResistant cells harboring the FLT3-ITD were developed by overexposure of MV4-11 to CEP-701, and the effects of 5-Aza treatment were investigated. Apoptosis and cytotoxicity of CEP-701 were determined using Annexin V and MTS assays, respectively. Gene expression was performed by quantitative real-time PCR. STATs activity was examined by western blotting and the methylation profile of SHP-1 was studied using MS-PCR and pyrosequencing analysis. Repeated-measures ANOVA and Kruskal-Wallis tests were used for statistical analysis.
resultsThe cytotoxic dose of CEP-701 on resistant cells was significantly higher in comparison with parental and MV4-11R-cep + 5-Aza cells (p = 0.004). The resistant cells showed a significant higher viability and lower apoptosis compared with other cells (p < 0.001). Expression of SHP-1 was 7-fold higher in MV4-11R-cep + 5-Aza cells compared to parental and resistant cells (p = 0.011). STAT3 was activated in resistant cells. Methylation of SHP-1 was significantly decreased in MV4-11R-cep + 5-Aza cells (p = 0.002).
conclusionsThe restoration of SHP-1 expression induces sensitivity towards CEP-701 and could serve as a target in the treatment of AML. Our findings support the hypothesis that, the tumor-suppressor effect of SHP-1 is lost due to epigenetic silencing and its re-expression might play an important role in re-inducing sensitivity to TKIs. Thus, SHP-1 is a plausible candidate for a role in the development of CEP-701 resistance in FLT3-ITD+ AML patients.
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