ArticleOncotarget2017
Increasing TIMP3 expression by hypomethylating agents diminishes soluble MICA, MICB and ULBP2 shedding in acute myeloid leukemia, facilitating NK cell-mediated immune recognition.
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 34 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
34 citing papers in PubMed, 45 citations in OpenAlex.
- Targeting the NKG2D axis in head and neck squamous cell carcinoma: from molecular insights to clinical applications.Cancer cell international · 2026Review
- Targeting the MICA/B-NKG2D axis in cancer: from molecular structure to immunotherapeutic strategies-a narrative review.Translational cancer research · 2026Review
- A potential mechanism of tumor immune escape: Regulation and application of soluble natural killer group 2 member D ligands (Review).Oncology reports · 2024Review
- The Role of Methylation in Chronic Lymphocytic Leukemia and Its Prognostic and Therapeutic Impacts in the Disease: A Systematic Review.Advances in hematology · 2024Review
- STAT3 in acute myeloid leukemia facilitates natural killer cell-mediated surveillance.Frontiers in immunology · 2024Article
- Cellular Composition and 5hmC Signature Predict the Treatment Response of AML Patients to Azacitidine Combined with Chemotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Effects of epigenetic therapy on natural killer cell function and development in hematologic malignancy.Journal of leukocyte biology · 2023Review
- Targets of Immune Escape Mechanisms in Cancer: Basis for Development and Evolution of Cancer Immune Checkpoint Inhibitors.Biology · 2023Review
- Beyond αβ T cells: NK, iNKT, and γδT cell biology in leukemic patients and potential for off-the-shelf adoptive cell therapies for AML.Frontiers in immunology · 2023Review
- Advancing CART therapy for acute myeloid leukemia: recent breakthroughs and strategies for future development.Frontiers in immunology · 2023Review
- NK cell defects: implication in acute myeloid leukemia.Frontiers in immunology · 2023Review
- Natural killer cells and acute myeloid leukemia: promises and challenges.Cancer immunology, immunotherapy : CII · 2022Review
- Article
- Tissue Inhibitor of Metalloproteases 3 (TIMP-3): In Vivo Analysis Underpins Its Role as a Master Regulator of Ectodomain Shedding.Membranes · 2022Review
- Natural Killer Cell-Mediated Immunotherapy for Leukemia.Cancers · 2022Review
- Article
- Review
- Efficacy and safety of decitabine combined with HAAG (homoharringtonine, aclarubicin, low-dose cytarabine and G-CSF) for newly diagnosed acute myeloid leukemia.Frontiers in oncology · 2022Article
- Stem cells-derived natural killer cells for cancer immunotherapy: current protocols, feasibility, and benefits of ex vivo generated natural killer cells in treatment of advanced solid tumors.Cancer immunology, immunotherapy : CII · 2021Review
- CAR-T Cell Therapy for Acute Myeloid Leukemia: Preclinical Rationale, Current Clinical Progress, and Barriers to Success.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2021Review
Corrections and comments
- Erratum issuedCorrection: Increasing TIMP3 expression by hypomethylating agents diminishes soluble MICA, MICB and ULBP2 shedding in acute myeloid leukemia, facilitating NK cell-mediated immune recognition.2018 · Puras, Alfredo Minguela [corrected to Minguela, Alfredo]
Authors and funding
15 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Acute myeloid leukemia (AML) is a disease with great morphological and genetic heterogeneity, which complicates its prognosis and treatment. The hypomethylating agents azacitidine (Vidaza®, AZA) and decitabine (Dacogen®, DAC) have been approved for the treatment of AML patients, but their mechanisms of action are poorly understood. Natural killer (NK) cells play an important role in the recognition of AML blasts through the interaction of the activating NKG2D receptor with its ligands (NKG2DL: MICA/B and ULBPs1-3). However, soluble NKG2DL (sNKG2DL) can be released from the cell surface, impairing immune recognition. Here, we examined whether hypomethylating agents modulate the release of sNKG2DL from AML cells. Results demonstrated that AZA- and DAC-treated AML cells reduce the release of sNKG2DL, preventing downregulation of NKG2D receptor on the cell surface and promoting immune recognition mediated by NKG2D-NKG2DL engagement. We show that the shedding of MICA, MICB and ULBP2 is inhibited by the increased expression of TIMP3, an ADAM17 inhibitor, after DAC treatment. The TIMP3 gene is highly methylated in AML cells lines and in AML patients (25.5%), in which it is significantly associated with an adverse cytogenetic prognosis of the disease. Overall, TIMP3 could be a target of the demethylating treatments in AML patients, leading to a decrease in MICA, MICB and ULBP2 shedding and the enhancement of the lytic activity of NK cells through the immune recognition mediated by the NKG2D receptor.
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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 OpenQuestion graph.