ArticleMolecular oncology2020
CCL5 mediates target-kinase independent resistance to FLT3 inhibitors in FLT3-ITD-positive AML.
Article in Molecular oncology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- The Inv(16) Oncogene CBFB::MYH11 is Required for the Survival of Leukemia Cells in the Blood and Spleen, but not the Bone Marrow.Oncogene · 2026Article
- The role of chemokine receptors in leukemia: implications for prognosis and therapeutic strategies.Molecular biology reports · 2026Review
- Functional combination of resveratrol and midostaurin induces cytotoxicity to overcome acquired midostaurin resistance in FLT3-ITD expressing acute myeloid leukemia cells.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- The Dual PIM/FLT3 Inhibitor MEN1703 Combines Synergistically With Gilteritinib in FLT3-ITD-Mutant Acute Myeloid Leukaemia.Journal of cellular and molecular medicine · 2024Article
- Dissecting L-glutamine metabolism in acute myeloid leukemia: single-cell insights and therapeutic implications.Journal of translational medicine · 2024Article
- CXCR4 as a therapeutic target in acute myeloid leukemia.Leukemia · 2024Review
- Review
- Establishment and verification of a TME prognosis scoring model based on the acute myeloid leukemia single-cell transcriptome.Scientific reports · 2024Article
- Overexpression of Nrf2 in bone marrow mesenchymal stem cells promotes B-cell acute lymphoblastic leukemia cells invasion and extramedullary organ infiltration through stimulation of the SDF-1/CXCR4 axis.Frontiers in pharmacology · 2024Article
- AML under the Scope: Current Strategies and Treatment Involving FLT3 Inhibitors and Venetoclax-Based Regimens.International journal of molecular sciences · 2023Review
- NADPH oxidase mediated oxidative stress signaling in FLT3-ITD acute myeloid leukemia.Cell death discovery · 2023Review
- Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure.Cancers · 2022Review
- Review
- Review
- HCK is a Potential Prognostic Biomarker that Correlates with Immune Cell Infiltration in Acute Myeloid Leukemia.Disease markers · 2022Article
- Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches.OncoTargets and therapy · 2022Review
- Strategies targeting FLT3 beyond the kinase inhibitors.Pharmacology & therapeutics · 2021Review
- Identification of Potential Novel Prognosis-Related Genes Through Transcriptome Sequencing, Bioinformatics Analysis, and Clinical Validation in Acute Myeloid Leukemia.Frontiers in genetics · 2021Article
- Dysregulation of miR-138-5p/RPS6KA1-AP2M1 Is Associated With Poor Prognosis in AML.Frontiers in cell and developmental biology · 2021Article
- The CCL5/CCR5 Axis in Cancer Progression.Cancers · 2020Review
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Authors and funding
12 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
FLT3-ITD tyrosine kinase inhibitors (TKI) show limited clinical activity in acute myeloid leukemia (AML) due to emerging resistance. TKI resistance is mediated by secondary FLT3-ITD mutations only in a minority of cases. We hypothesize that the cytokine CCL5 protects AML cells from TKI-mediated cell death and contributes to treatment resistance. We generated PKC412- and sorafenib-resistant MOLM-13 cell lines as an in vitro model to study TKI resistance in AML. Increased CCL5 levels were detected in supernatants from PKC412-resistant cell lines compared to TKI-sensitive cells. Moreover, CCL5 treatment of TKI-sensitive cells induced resistance to PKC412. In resistant cell lines with high CCL5 release, we observed a significant downregulation of the CCL5-receptor CCR5 and CXCR4. In these cell lines, TKI resistance could be partly overcome by addition of the CXCR4-receptor antagonist plerixafor. Microarray and intracellular flow cytometry analyses revealed increased p-Akt or p-Stat5 levels in PKC412-resistant cell lines releasing high amounts of CCL5. Treatment with the CXCR4 antagonist plerixafor, αCCL5, or CCR5-targeting siRNA led to a decrease of p-Akt-positive cells. Transient transfection of sensitive MOLM-13 cells with a CCL5-encoding vector mediated resistance against PKC412 and led to an increase in p-Akt-positive and p-Stat5-positive cells. Isolated AML blasts from patients treated with PKC412 revealed that CCL5 transcript levels increase significantly at relapse. Taken together, our findings indicate that CCL5 mediates resistance to FLT3-TKIs in FLT3-ITD-mutated AML and could possibly serve as a biomarker to predict drug resistance.
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