ArticleBlood2017
Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice.
Article in Blood, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 34 citations in OpenAlex.
- Heat Shock Protein 90: From Molecular Chaperone Function to Therapeutic Targeting in Malignancies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- EZH2 and intracellular CaCellular & molecular immunology · 2026Article
- Impact of Novel Agents on Allogeneic Hematopoietic Cell Transplantation in Patients with T-Cell Lymphomas.Cells · 2025Review
- Intrinsic RIG-I restrains STAT5 activation to modulate antitumor activity of CD8+ T cells.The Journal of clinical investigation · 2023Article
- HSP90-Dependent Upregulation of EZH2 Promotes Hypoxia/Reoxygenation-Induced Pyroptosis by Inhibiting miR-22 in Endothelial Cells.Journal of inflammation research · 2023Article
- Dissecting the regulatory network of transcription factors in T cell phenotype/functioning during GVHD and GVT.Frontiers in immunology · 2023Review
- The pleiotropic roles of EZH2 in T-cell immunity and immunotherapy.International journal of hematology · 2022Review
- Article
- Autologous treatment for ALS with implication for broad neuroprotection.Translational neurodegeneration · 2022Article
- Observational
- CD11c participates in triggering acute graft-versus-host disease during bone marrow transplantation.Immunology · 2021Article
- Post-translational modifications of EZH2 in cancer.Cell & bioscience · 2020Review
- Modulating the Heat Sensitivity of Prostate Cancer Cell Lines In Vitro: A New Impact for Focal Therapies.Biomedicines · 2020Article
- Inhibition of EZH2 ameliorates bacteria-induced liver injury by repressing RUNX1 in dendritic cells.Cell death & disease · 2020Article
- Targeting Histone Deacetylases to Modulate Graft-Versus-Host Disease and Graft-Versus-Leukemia.International journal of molecular sciences · 2020Review
- 17-Aminogeldanamycin Inhibits Constitutive Nuclear Factor-Kappa B (NF-κB) Activity in Patient-Derived Melanoma Cell Lines.International journal of molecular sciences · 2020Article
- Somatic mTOR mutation in clonally expanded T lymphocytes associated with chronic graft versus host disease.Nature communications · 2020Article
- Heat-shock proteins: chaperoning DNA repair.Oncogene · 2020Review
- B cells in chronic graft-versus-host disease.Human immunology · 2019Review
- Control of Intra-Thymic αβ T Cell Selection and Maturation by H3K27 Methylation and Demethylation.Frontiers in immunology · 2019Review
Corrections and comments
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Authors and funding
19 authors at 8 institutions in 2 countries.
Funding
Abstract
Modulating T-cell alloreactivity has been a main strategy to reduce graft-versus-host disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem-cell transplantation (HSCT). Genetic deletion of T-cell Ezh2, which catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3), inhibits GVHD. Therefore, reducing Ezh2-mediated H3K27me3 is thought to be essential for inhibiting GVHD. We tested this hypothesis in mouse GVHD models. Unexpectedly, administration of the Ezh2 inhibitor GSK126, which specifically decreases H3K27me3 without affecting Ezh2 protein, failed to prevent the disease. In contrast, destabilizing T-cell Ezh2 protein by inhibiting Hsp90 using its specific inhibitor AUY922 reduced GVHD in mice undergoing allogeneic HSCT. In vivo administration of AUY922 selectively induced apoptosis of activated T cells and decreased the production of effector cells producing interferon γ and tumor necrosis factor α, similar to genetic deletion of Ezh2. Introduction of Ezh2 into alloreactive T cells restored their expansion and production of effector cytokines upon AUY922 treatment, suggesting that impaired T-cell alloreactivity by inhibiting Hsp90 is achieved mainly through depleting Ezh2. Mechanistic analysis revealed that the enzymatic SET domain of Ezh2 directly interacted with Hsp90 to prevent Ezh2 from rapid degradation in activated T cells. Importantly, pharmacological inhibition of Hsp90 preserved antileukemia activity of donor T cells, leading to improved overall survival of recipient mice after allogeneic HSCT. Our findings identify the Ezh2-Hsp90 interaction as a previously unrecognized mechanism essential for T-cell responses and an effective target for controlling GVHD.
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Registered trials
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