Academic literature on the topic 'EZH2i'
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Journal articles on the topic "EZH2i"
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Preston, Samuel E. J., Audrey Emond, Filippa Pettersson, Daphné Dupéré-Richer, Madelyn Jean Abraham, Alberto Riva, Mena Kinal, et al. "Acquired Resistance to EZH2 Inhibitor GSK343 Promotes the Differentiation of Human DLBCL Cell Lines toward an ABC-Like Phenotype." Molecular Cancer Therapeutics 21, no. 4 (January 27, 2022): 511–21. http://dx.doi.org/10.1158/1535-7163.mct-21-0216.
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Abstract Diffuse large B-cell lymphoma (DLBCL) accounts for 40% of non-Hodgkin lymphoma, and 30% to 40% of patients will succumb to relapsed/refractory disease (rrDLBCL). Patients with rrDLBCL generally have low long-term survival rates due to a lack of efficient salvage therapies. Small-molecule inhibitors targeting the histone methyltransferase EZH2 represent an emerging group of novel therapeutics that show promising clinical efficacy in patients with rrDLBCL. The mechanisms that control acquired resistance to this class of targeted therapies, however, remain poorly understood. Here, we develop a model of resistance to the EZH2 inhibitor (EZH2i) GSK343 and use RNA-seq data and in vitro investigation to show that GCB (germinal center B-cell)-DLBCL cell lines with acquired drug resistance differentiate toward an ABC (activated B-cell)-DLBCL phenotype. We further observe that the development of resistance to GSK343 is sufficient to induce cross-resistance to other EZH2i. Notably, we identify the immune receptor SLAMF7 as upregulated in EZH2i-resistant cells, using chromatin immunoprecipitation profiling to uncover the changes in chromatin landscape remodeling that permit this altered gene expression. Collectively, our data reveal a previously unreported response to the development of EZH2i resistance in DLBCL, while providing strong rationale for pursuing investigation of dual-targeting of EZH2 and SLAMF7 in rrDLBCL.
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Zhang, Yiqun, Lanlan Zhou, Safran Howard, Attila Seyhan, and Wafik El-Deiry. "DDRE-16. SYNERGISTIC TUMOR SUPPRESSION FROM COMBINATION OF ONC201 AND EPIGENETIC MODULATORS EZH2 OR HDAC INHIBITOR PROVIDES A NOVEL TREATMENT STRATEGY FOR GBM AND DMG." Neuro-Oncology 22, Supplement_2 (November 2020): ii64—ii65. http://dx.doi.org/10.1093/neuonc/noaa215.261.
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Abstract ONC201 is a promising anti-cancer agent that kills tumor cells by triggering an integrated stress response (ISR) dependent on ATF4. ONC201 demonstrated tumor regression and prolonged disease stability in patients with histone H3K27M-mutated midline glioma. The Enhancer of Zeste Homolog 2 (EZH2), a subunit of the polycomb repressive complex 2 (PRC2), is a histone methyltransferase that tri-methylates H3K27 (H3K27me3) and silences target genes. EZH2 inhibitors (EZH2i) reduce global H3K27 methylation. Based on the fact that the H3K27 mutation reduces H3K27 dimethylation (H3K27me2) and trimethylation (H3K27me3), we hypothesized that ONC201 sensitivity and tumor cell death may be enhanced by reducing H3K27 methylation with EZH2i as a mimic of H3K27M-mutation and by increasing H3K27 acetylation with histone deacetylase inhibitors (HDACi). We evaluated synergy of EZH2i EPZ-6438 or HDACi vorinostat with ONC201 against GBM cell lines, U251 and T98G-1 and DMG cell line, SF8638. Cell viability was determined with the Cell Titer Glo assay. Apoptosis was evaluated through immunoblotting of cleaved PARP and flow cytometry analysis of cell distribution. ISR activity was evaluated using immunoblotting of ATF4. Our result demonstrate that ONC201 synergistically reduced cell viability with vorinostat in U251, T98G-1 and SF8628 cell lines, induced apoptosis in combination with vorinostat in U251 and SF8628. ONC201 synergistically reduced cell viability and induced apoptosis with EPZ-6438 in U251. The immunoblotting detected no enhancement of ATF4 by addition of EPZ-6438 to ONC201. Immunoblotting analysis showed that EPZ-6438 reduced H3K27me3 in U251. Our results unravel potent synergy between ONC201 and EZH2i or HDACi in GBM and DMG cell lines, and provide further insights into the role of H3K27me3 in ONC201 drug sensitivity.
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Kosoff, David, Leigh Ellis, David J. Beebe, and Joshua Michael Lang. "Targeting tumor-associated macrophage (TAM) mediated inhibition of T-cell migration in prostate cancer using epigenetic modifying agents." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): 166. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.166.
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166 Background: Cytotoxic T lymphocytes (CTLs) perform vital anti-tumor functions and are critical to the efficacy of many anticancer therapies. In prostate cancer, the characteristic paucity of activated CTLs within the tumor microenvironment (TME) may be a key factor in disease progression and likely underlies the limited role for immune checkpoint inhibitors (ICIs) in prostate cancer treatment. In this study, we utilized novel microfluidic technologies to evaluate whether TAMs may be driving the exclusion of T cells from the prostate TME and whether the immunosuppressive functions of TAMs could be modified by epigenetic modifying agents. Methods: Primary macrophages and autologous T cells were derived from peripheral blood samples of prostate cancer patients at the University of Wisconsin. Mono-, co-, and tri-culture systems of macrophages, T cells, and 22RV1 cells (androgen-dependent prostate cancer cell line) were cultured in 2D and 3D in microfluidic cell culture platforms. Culture systems were treated with the EZH2 inhibitors (EZH2i) DZNep or EPZ-6438 or left untreated. Macrophages were also treated with M1 (IFN-g) and M2 (IL-4) polarizing cytokines. Systems were analyzed for T cell migration as well as mRNA and protein expression in each cell population. Results: Autologous macrophages inhibited activated T cell migration towards tumor cells in a multi-cellular microscale TME. T cell migration was restored through treatment with EZH2i. Gene expression analysis identified that EZH2i altered macrophage gene expression in the unpolarized and M1/M2 polarized states. In particular, there was increased expression of genes involved in T cell recruitment/chemotaxis, including CXCL10, CXCL11, CXCL12, following EZH2i treatment. Conclusions: We used novel microfluidic technologies to model and analyze multicellular TMEs using primary, patient-derived cells. We demonstrate that TAM-mediated suppression of T cell migration is mediated, in part, through epigenetic pathways, which can be targeted with EZH2i. Treatment with EZH2i, alone or in combination other therapies such as ICIs, may enhance cytotoxic T cell migration and activity in primary prostate cancer.
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Pawlyn, Charlotte, Michael Bright, Amy Buros, Caleb K. Stein, Zoe Walters, Lauren Aronson, Fabio Mirabella, et al. "Inhibition of the Epigenetic Modifier EZH2 Upregulates Cell Cycle Control Genes to Inhibit Myeloma Cell Growth and Overcome High-Risk Disease Features." Blood 128, no. 22 (December 2, 2016): 3289. http://dx.doi.org/10.1182/blood.v128.22.3289.3289.
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Abstract Introduction High expression of the H3K27 histone methyltransferase EZH2 mRNA in myeloma (MM) patient samples is associated with molecular features of high risk disease, including increased proliferation, and adverse outcomes (1). Mutations or deletions in the H3K27 demethylase KDM6A are associated with similar findings (2) and would be expected to have the same epigenetic effect, increasing H3K27me3 levels, a mark associated with repression of gene expression. We, therefore, sought to identify the role EZH2 plays in controlling myeloma cell proliferation. Methods A panel of MM cell lines and primary patient samples (CD138 selected from bone marrow with consent) representing a variety of different MM molecular subgroups were used. Cell viability (WST-1), cell cycle (PI) and apoptosis (AnnexinV/PI, Caspase-Glo 3/7) assays were performed. Affymetrix gene expression arrays followed by validation with RT-PCR were used to identify patterns of gene expression change with EZH2i. Western blotting confirmed changes at the protein level and Chip-PCR was performed using a validated antibody and isotype control to identify H3K27me3 changes at the relevant gene promotors. Affymetrix gene expression data for 1213 patients enrolled in the Total Therapy studies were used to investigate the relevance of our findings in myeloma patient samples. Results We confirmed a reduction in viability following EZH2i using two chemically distinct, specific small molecule inhibitors (EPZ005687 and UNC1999) and the negative control compound UNC2400. There was a reduction in viability in 6/8 cell lines and 5/6 patient samples. Response to inhibition was not related to molecular subgroup or the presence of high-risk molecular features including del17p. Global levels of H3K27me3 measured by Western blot were reduced in all cell lines regardless of response to EZH2i. In responding cell lines EZH2i induced cell cycle arrest at G1/S followed by induction of apoptosis. Gene expression arrays performed using mRNA from KMS11 and KMM1 cell lines highlighted a change in expression of cell cycle control genes associated with EZH2i. This finding was validated using qRT-PCR, which demonstrated upregulation of the cyclin dependent kinase inhibitors CDKN2B, CDKN1A or both. These findings were confirmed at the protein level by Western blotting. Chip-PCR experiment using cell lysates from KMS11 cells following incubation with EZH2i over 6 days identified changes in H3K27me3 at the promoter and transcriptional start site (PROM/TSS) regions of the CDKN2B and CDKN1A genes. The most specific changes occurred at the CDKN1A PROM/TSS, which were more heavily marked with H3K27me3 at baseline compared to a region approx. 5KB upstream. Given these results, which suggest that CDKN1A expression may be controlled by changes in H3K27me3, we explored the effect of CDKN1A mRNA expression in our patient datasets. We found the expression of EZH2 and CDKN1A to be inversely correlated (R=-0.170, p<0.0001) and that low expression of CDKN1A was associated with a significantly shorter progression free and overall survival (p<0.001). In order to confirm whether these gene expression changes could be used as a potential biomarker of response we looked at our panel of cell lines with variable responses to EZH2i. We identified a consistent increase in expression of CDKN1A only in responding cell lines suggesting it could be used as a biomarker of efficacy in the clinic. Conclusions These data support the hypothesis that CDKN1A expression is suppressed by increased H3K27me3, due to high expression of EZH2 and that this can be reversed with pharmacological EZH2 inhibition leading to a reduction in proliferation of myeloma cells. We provide data which supports the investigation of EZH2i in clinical trials of myeloma patients, which has the potential to be an effective therapeutic strategy even for those with high-risk disease, for whom current treatment approaches are ineffective.Pawlyn et al, EZH2 Overexpression in Myeloma Patients Shortens Survival and in-vitro Data Supports a Potential New Targeted Treatment Strategy. AACR and IMW abstracts, 2015Pawlyn et al, The Spectrum and Clinical Impact of Epigenetic Modifier Mutations in Myeloma. Clinical Cancer Research, 2016 Disclosures Pawlyn: Celgene: Consultancy, Honoraria, Other: Travel Support; Takeda Oncology: Consultancy. Kaiser:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS: Consultancy, Other: Travel Support; Takeda: Consultancy, Other: Travel Support; Chugai: Consultancy. Jones:Celgene: Honoraria, Research Funding. Jackson:Amgen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau. Bergsagel:Novartis: Research Funding; Amgen, BMS, Novartis, Incyte: Consultancy. Morgan:Univ of AR for Medical Sciences: Employment; Janssen: Research Funding; Bristol Meyers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Davies:Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.
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Sriramkumar, Shruthi, Tara X. Metcalfe, Tim Lai, Xingyue Zong, Fang Fang, Heather M. O’Hagan, and Kenneth P. Nephew. "Single-cell analysis of a high-grade serous ovarian cancer cell line reveals transcriptomic changes and cell subpopulations sensitive to epigenetic combination treatment." PLOS ONE 17, no. 8 (August 3, 2022): e0271584. http://dx.doi.org/10.1371/journal.pone.0271584.
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Ovarian cancer (OC) is a lethal gynecological malignancy with a five-year survival rate of only 46%. Development of resistance to platinum-based chemotherapy is a common cause of high mortality rates among OC patients. Tumor and transcriptomic heterogeneity are drivers of platinum resistance in OC. Platinum-based chemotherapy enriches for ovarian cancer stem cells (OCSCs) that are chemoresistant and contribute to disease recurrence and relapse. Studies examining the effect of different treatments on subpopulations of HGSOC cell lines are limited. Having previously demonstrated that combined treatment with an enhancer of zeste homolog 2 inhibitor (EZH2i) and a RAC1 GTPase inhibitor (RAC1i) inhibited survival of OCSCs, we investigated EZH2i and RAC1i combination effects on HGSOC heterogeneity using single cell RNA sequencing. We demonstrated that RAC1i reduced expression of stemness and early secretory marker genes, increased expression of an intermediate secretory marker gene and induced inflammatory gene expression. Importantly, RAC1i alone and in combination with EZH2i significantly reduced oxidative phosphorylation and upregulated Sirtuin signaling pathways. Altogether, we demonstrated that combining a RAC1i with an EZH2i promoted differentiation of subpopulations of HGSOC cells, supporting the future development of epigenetic drug combinations as therapeutic approaches in OC.
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Carrancio, Soraya, Celia Fontanillo, Ryan Galasso, Martino Colombo, Scott Wood, Carla Guarinos, Alejandro Panjkovich, et al. "Abstract 3932: Pathway interaction and mechanistic synergy of CC-99282, a novel cereblon E3 ligase modulator (CELMoD) agent, with enhancer of zeste homolog 2 inhibitors (EZH2is)." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3932. http://dx.doi.org/10.1158/1538-7445.am2022-3932.
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Abstract CC-99282 is a novel CELMoD® agent that was optimized for activity in non-Hodgkin lymphoma (NHL). CC-99282 potently degrades Ikaros and Aiolos, resulting in enhanced antiproliferative, apoptotic, and immune-stimulatory activity in diffuse large B-cell lymphoma (DLBCL) models, including those with acquired chemoresistance (Lopez-Girona A, et al. Hematol Oncol. 2021). In lymphocytes, Ikaros negatively regulates gene expression via histone modifications, including polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) (Oravecz A, et al. Nat Commun. 2015); in NHL, these epigenetic mechanisms are unclear. Using DLBCL models, we explored the relationship between CC-99282 activity and epigenetic status, and the mechanism of synergy of CC-99282 treatment and inhibition of EZH2, a PRC2 component. Baseline characteristics of human DLBCL lines and effects of CC-99282 ± tazemetostat (TAZ), a representative EZH2i, were evaluated in vitro and in vivo by chromatin immunoprecipitation sequencing, gene expression, flow cytometry, immunoblotting, enzyme fragment complementation assays, and/or CRISPR/Cas9 gene editing. Analysis of Ikaros/Aiolos degradation in > 20 DLBCL cell lines showed their loss is necessary, but not sufficient for CC-99282 efficacy. Evaluation of baseline histone marks showed that the sensitive cell lines exhibit aberrant, higher H3K27me3 coverage at promoter regions of expressed genes. This suggests a direct correlation between H3K27me3 status at these regions and CC-99282 sensitivity. In T cells, Oravecz et al. found that loss of Ikaros reduces H3K27me3 at specific chromatin sites due to its interaction with PRC2. We confirmed that these affected regions are enriched in genes upregulated upon CC-99282 treatment in DLBCL cell lines, suggesting a similar role for Ikaros in DLBCL. Pathway analysis following CC-99282 or TAZ treatment demonstrated high overlap between pathways altered by both agents. CC-99282 + TAZ combined demonstrated additive and/or synergistic antiproliferative and apoptotic effects in DLBCL cell lines. This combination did not alter Ikaros degradation or overall H3K27me3 status but increased downstream effects. Results were confirmed by CRISPR/Cas9 knockout competition assays with EZH2 and other PRC2 components. This effect was independent of cell of origin, EZH2 mutational status, or degree of CC-99282 sensitivity. Synergy was confirmed using the SU-DHL6 and DB xenograft models that are intrinsically resistant to EZH2is and CC-99282, respectively. Combination treatment yielded durable responses and tumor-free animals. Collectively, these data suggest that Ikaros could act as an epigenetic modulator through PRC2 recruitment and support the combination of CC-99282 with EZH2is in NHL (NCT03930953) to favor broad and durable clinical responses. Citation Format: Soraya Carrancio, Celia Fontanillo, Ryan Galasso, Martino Colombo, Scott Wood, Carla Guarinos, Alejandro Panjkovich, Diana Jankeel, Adam Blattler, Preethi Janardhanan, Matthew Groza, Jim Leisten, Rama Krishna Narla, Antonia Lopez-Girona, Daniel W. Pierce. Pathway interaction and mechanistic synergy of CC-99282, a novel cereblon E3 ligase modulator (CELMoD) agent, with enhancer of zeste homolog 2 inhibitors (EZH2is) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3932.
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Wang, Zhiquan, Justin C. Boysen, Huihuang Yan, Charla R. Secreto, Sameer A. Parikh, Saad S. Kenderian, Wei Ding, Esteban Braggio, Susan L. Slager, and Neil E. Kay. "Targeting Aberrant Chromatin in Chronic Lymphocytic Leukemia." Blood 136, Supplement 1 (November 5, 2020): 1. http://dx.doi.org/10.1182/blood-2020-140309.
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Introduction: Chronic Lymphocytic Leukemia (CLL) is characterized by the accumulation of mature-appearing malignant lymphocytes (CLL B-cells) in the blood, marrow, lymph nodes, and spleen. Despite improved outcome with the introduction of novel BCR and BCL-2 inhibitors, disease progression is still a therapeutic challenge from either differential responses or acquired drug resistance. Recent studies in CLL reported alterations of the epigenetic landscape as well as mutations of genes encoding key chromatin machineries. These aberrant chromatin structures may provide novel therapeutic targets for CLL. Here, we identify aberrant chromatin features in CLL B-cells as novel therapeutic targets. Methods: Histones were extracted by acid from B cells derived from 10 random selected CLL patients and 10 normal donors and histone modifications were checked by western blot. For ChIP-seq study, published H3K27me3 ChIP-seq data (GSE113336) were downloaded from and analyzed (Control samples, n= 6; CLL samples, n=16). Gene ontology analysis used the Panther Classification System. Cell Survival was determined by CellTiter 96® AQueous Assay (Promega). Results: While most histone modifications do not vary between CLL and controls, H3K27me3 and H3.3S31ph are increased and decreased respectively, albeit variably, in CLL B-cells (Fig1. A and B). Notably, the low level of H3.3S31ph was observed in a subset of samples (7 of 10 CLL samples tested). To further investigate the biology and role of H3K27me3 in CLL, we analyzed its genome-wide distribution by chromatin immunoprecipitation followed by sequencing (ChIP-seq). Our analysis showed that the genes with increased H3K27me3 occupancy were mostly enriched in tumor suppression pathways (e.g., negative regulation of PI3K-Akt pathway) or down-regulated genes in CLL such as genes involved in the pro-apoptotic pathway (FAS) (Fig1. C and D). These results suggested that high enrichment of H3K27me3 may regulate the expression of these genes, contributing to CLL survival. H3K27 methylation, an important suppressive histone modification that is associated with transcription repression, is catalyzed by Polycomb Repressive Complex 2 (PRC2). Therefore, inhibition of Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of PRC2, could be explored as a therapy approach in CLL. However, feedback activation of H3K27 acetylation (H3K27ac) can promote expression of pro-survival genes that confers EZH2 inhibitor (EZH2i) resistance, which limits its use in human malignancy. Thus, the epigenetic determinants that reliably overcome EZH2i resistance or sensitize cells to EZH2 inhibition have yet to be identified. As we observed that the CLL B-cells in a subset of CLL patients have low levels of H3.3S31ph, and a recent study showed the importance of H3.3S31ph for the enzymatic activity of p300 to acetylate H3 at lysine 27(Martire S et al., Nat Genet. 2019), we assessed the role of H3.3S31ph in the process of EZH2 inhibitor-mediated H3K27ac. Our results showed that inhibition of H3.3S31ph by CHK1 inhibitor MK-8776 abolished the activation of H3K27ac by EZH2i in MEC1 cells, which represents the patients who have CLL cells with relatively high level H3.3S31ph. However, we did not see a major increase of H3K27ac and H3.3S31ph in primary CLL B-cells with EZH2 inhibition (Fig. 1E), consistent with the relatively low expression of CHK1 protein in these cells (Fig. 1F). Because our data shows the requirement of H3.3S31ph in H3K27ac activation by EZH2 inhibition, we next tested if H3.3S31ph inhibition could overcome H3K27ac induced EZH2 inhibition resistance. We found that suppression of H3.3S31ph by CHK1 inhibitor MK-8776 sensitizes the CLL-like line MEC1 to EZH1/2 inhibition (Fig. 1 G). We then showed that an EZH2 inhibitor, Valemetostat, reduce the survival of the primary CLL B-cells (Fig. 1 H). These results suggest that the low level of H3.3S31ph may provide a therapeutic opportunity for CLL treatment with EZH inhibition. Conclusion: In summary, we have elucidated how epigenetic features in leukemic CLL B-cells (H3K27me3 and H3.3S31ph), can provide novel treatment targets for CLL (Fig. 1 I). Moreover, this study may provide a proof of concept to develop new treatment strategies based on epigenetic vulnerabilities in other hematological malignancies. Disclosures Parikh: GlaxoSmithKline: Honoraria; MorphoSys: Research Funding; Genentech: Honoraria; Ascentage Pharma: Research Funding; AbbVie: Honoraria, Research Funding; TG Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Verastem Oncology: Honoraria; Merck: Research Funding. Kenderian:Kite: Research Funding; MorphoSys: Research Funding; Tolero: Research Funding; Humanigen: Consultancy, Patents & Royalties, Research Funding; BMS: Research Funding; Gilead: Research Funding; Juno: Research Funding; Lentigen: Research Funding; Mettaforge: Patents & Royalties; Novartis: Patents & Royalties, Research Funding; Torque: Consultancy; Sunesis: Research Funding. Ding:Beigene: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; DTRM: Research Funding; Abbvie: Research Funding. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Kay:Oncotracker: Membership on an entity's Board of Directors or advisory committees; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; MEI Pharma: Research Funding; Abbvie: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding.
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Cannito, Sara, Health Biology, Ornella Cutaia, Carolina Fazio, Maria Fortunata Lofiego, Francesca Piazzini, Laura Solmonese, Luana Calabrò, Michele Maio, and Alessia Covre. "844 Immunomodulatory activity of epigenetic drugs combinations in mesothelioma: laying the ground for new immunotherapeutic strategies." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A896. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0844.
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BackgroundGrowing evidence are demonstrating the therapeutic efficacy of immune checkpoint inhibitors (ICI) in mesothelioma; however, a limited percentage of patients benefits from this therapeutic approach. Epigenetic modifications play a relevant role in negatively regulating the cross-talk between neoplastic and immune cells, and in contributing to the highly immunosuppressive mesothelioma microenvironment. A better understanding of mesothelioma epigenetic landscape could open the path to novel and potentially more effective approaches combining ICI and epigenetic drugs. We investigated the immunomodulatory potential of epigenetic agents by comparing the activity of DNA hypomethylating agents (DHA) with histone deacetylases inhibitors (HDACi) and EZH2 inhibitors (EZH2i), alone or combined with DHA, in mesothelioma cells.MethodsFour mesothelioma cell lines were treated with the DHA guadecitabine 1μM, or with the HDACi, Valproic Acid (VPA) 1mM, or the EZH2i, EPZ-6438 1μM, alone or combined with guadecitabine. We investigated the expression of HLA class I molecules by flow-cytometry and of PD-L1, cancer testis antigens (CTA: NY-ESO, MAGE-A1), Natural Killer Group 2 member D Ligands (NKG2DLs: MIC-A, MIC-B, ULBP2) and EMT-regulating cadherins (CDH1, CDH2) by quantitative Real-Time PCR. Fold change (FC) expression for each treatment vs untreated cells was reported as mean values (FCm) among investigated cell lines. A positive modulation of the expression was considered if FCm>1.5.ResultsGuadecitabine upregulated the expression of HLA class I antigens (FCm=1.75), PD-L1 (FCm=2.38), NKG2DLs (MIC-A FCm=1.96, MIC-B FCm=2.57, and ULBP2 FCm=3.56), and upregulated/induced CTA expression. Similarly, VPA upregulated HLA class I antigens (FCm=1.67), PD-L1 (FCm=3.17), NKG2DLs (MIC-A FCm=1.78, MIC-B FCm=3.04, and ULBP2 FCm=3.75) expression; however, CTA expression was modulated only in 1 mesothelioma cell line. Conversely, EPZ-6438 up-regulated only NY-ESO-1 and MIC-B expression in 1 mesothelioma cell line.The addition of both VPA and EPZ-6483 to guadecitabine strengthened its immunomodulatory activity. Specifically, guadecitabine plus VPA or EPZ-6438 upregulated the expression of HLA class I antigens FCm=2.55 or 2.69, PD-L1 FCm=8.04 or 2.65, MIC-A FCm=3.81 or 2.26, MIC-B FCm=8.00 or 3.03, ULBP2 FCm=6.24 or 4.53, respectively. Higher levels of CTA upregulation/induction were observed with combination treatments vs guadecitabine alone.Cadherins modulation was mesothelioma histotype-related: CDH1 expression was induced in the 2 constitutively-negative sarcomatoid mesothelioma cells by guadecitabine alone or combined with VPA or EPZ-6438; CDH2 expression was upregulated by VPA alone (FCm=1.53) or plus guadecitabine (FCm=2.54).ConclusionsCombination of DHA-based immunotherapies with other classes of epigenetic drugs could be an effective strategy to be pursued in the mesothelioma clinic.
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Aoyama, Kazumasa, Makiko Mochizuki-Kashio, Motohiko Oshima, Shuhei Koide, Yaeko Nakajima-Takagi, Mitsutaka Maeda, Goro Sashida, and Atsushi Iwama. "Role of the Polycomb Methyltransferase Ezh1 in Myelodysplastic Syndrome Induced By Ezh2 Insufficiency." Blood 128, no. 22 (December 2, 2016): 1968. http://dx.doi.org/10.1182/blood.v128.22.1968.1968.
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Abstract Ezh1 and Ezh2, the catalytic components of polycomb-repressive complex 2 (PRC2), negatively control gene expression by catalyzing mono, di, and tri-methylation of histone H3 at lysine 27 (H3K27me1/me2/me3). Loss-of-function mutations of EZH2, but not those of EZH1, have been found in patients with hematologic malignancies such as myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), and MDS/MPN overlap disorders. We previously demonstrated that hematopoietic cell-specific Ezh2 knockout mice (Ezh2Δ/Δ) developed hematologic malignancies including MDS and MDS/MPN. Although deletion of Ezh1, another enzymatic component of PRC2, (Ezh1-/-) did not significantly affect global H3K27me3 levels or hematopoiesis, deletion of both Ezh1 and Ezh2 in mice (Ezh1-/-Ezh2Δ/Δ) caused rapid exhaustion of hematopoietic stem cells (HSCs). Given that only Ezh1 and Ezh2 are known as enzymatic components of PRC2, we concluded that residual PRC2 enzymatic activity is required for HSC maintenance and development of hematologic malignancies in the setting of EZH2 insufficiency frequently observed in MDS. However, the role of Ezh1 in Ezh2-insufficient hematologic malignancies is still not fully understood since hematopoiesis could not be maintained in Ezh1-/-Ezh2Δ/Δ mice. Here we analyzed the impact of Ezh1 heterozygosity on Ezh2-null hematopoiesis (Ezh1+/-Ezh2Δ/Δ), in which PRC2 activity is mediated by a single allele of Ezh1, for better understanding of Ezh2-deficient hematologic malignancies. We first transplanted BM cells from Ezh1+/-Ezh2flox/flox CD45.2 mice with CD45.1 wild-type competitor cells into lethally irradiated CD45.1 recipient mice and deleted Ezh2 by intraperitoneal injection of tamoxifen. Ezh1+/-Ezh2Δ/Δ cells exhibited a lower repopulation capacity than Ezh2Δ/Δ but established persistent repopulation for at least 6 months after the deletion of Ezh2 while double knockout cells (Ezh1-/-Ezh2Δ/Δ) were outcompeted by competitor cells immediately. We next transplanted BM cells from Ezh1+/-Ezh2flox/flox CD45.2 mice without CD45.1 wild-type competitor cells into lethally irradiated CD45.1 recipient mice and deleted Ezh2 by intraperitoneal injection of tamoxifen. Importantly, recipient mice reconstituted with Ezh1+/-Ezh2Δ/Δ cells exhibited MDS-like phenotypes including anemia and morphological myelodysplasia, which were more pronounced than those of Ezh2Δ/Δ mice. Ezh1+/-Ezh2Δ/Δ mice also showed more advanced hematological abnormalities such as erythroid differentiation block, increased apoptosis of erythroid cells, and extramedullary hematopoiesis in the spleen than Ezh2Δ/Δ mice did. These results suggest that Ezh1 heterozygosity promotes the development of myelodysplasia in the setting of Ezh2insufficiency. Next we examined the molecular mechanism by which the loss of Ezh1 promotes myelodysplasia. Western blot and ChIP-sequence analyses revealed that global levels of H3K27me3 were not significantly changed but H3K27me3 levels at promoter regions of the PRC2 target genes were obviously reduced by Ezh1 heterozygosity in Ezh2Δ/Δ HSPCs. As a consequence, PRC2 target genes were highly de-repressed in Ezh1+/-Ezh2Δ/Δ LSK HSPCs compared with Ezh2Δ/Δ HSPCs. Among these, several genes appeared to be associated with MDS such as S100A9, encoding an inflammatory protein implicated in dyserythropoiesis in MDS. Furthermore, gene set enrichment analysis showed that the genes highly expressed in myeloid cells were positively enriched by Ezh1 heterozygosity in Ezh2Δ/ΔHSPCs. These findings indicate that dosage of Ezh1 is critical in the maintenance of Ezh2-insufficient hematopoiesis as well as the progression of MDS with Ezh2 insufficiency. Disclosures No relevant conflicts of interest to declare.
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Tanaka, Satomi, Goro Sashida, Satoru Miyagi, Koutaro Yokote, Chiaki Nakaseko, and Atsushi Iwama. "Ezh2 Plays a Critical Role in the Progression of MLL-AF9-Induced Acute Myeloid Leukemia." Blood 118, no. 21 (November 18, 2011): 57. http://dx.doi.org/10.1182/blood.v118.21.57.57.
Full textAbstract:
Abstract Abstract 57 The polycomb group proteins function in gene silencing through histone modifications. They have been characterized as a general regulator of stem cells, but also play a critical role in cancer. EZH2 is a catalytic component of the polycomb repressive complex 2 (PRC2) and tri-methylates histone H3 at lysine 27 to transcriptionally repress the target genes. Although EZH2 is over-expressed in various cancers including hematological malignancies, it remains unknown how EZH2 contributes to the initiation and/or progression of acute myeloid leukemia (AML). To understand the role of EZH2 in AML, we transformed granulocyte macrophage progenitors (GMPs) from Cre-ERT;Ezh2+/+ and Cre-ERT;Ezh2flox/flox mice with the MLL-AF9 fusion gene. Then, Ezh2 was deleted by inducing nuclear translocation of Cre by adding tamoxifen to culture. We found that proliferation of Ezh2δ/δ transformed cells was severely compromised upon deletion of Ezh2 (Ezh2δ/δ) in liquid culture. They gave rise to a significantly reduced number of colonies in replating assays. Of note, while Ezh2+/+ cells formed compact colonies composed of immature myeloblasts, Ezh2δ/δ cells formed dispersed colonies composed of differentiated myeloid cells. We next transplanted Cre-ERT;Ezh2+/+ and Cre-ERT;Ezh2flox/flox GMPs transformed by MLL-AF9 into recipient mice. All the recipient mice developed AML by 3 weeks after transplantation. At 3 weeks after transplantation, we depleted Ezh2 by intraperitoneal injection of tamoxifen. Deletion of Ezh2 significantly prolonged the survival of the recipient mice (60 days vs. 76 days, p<0.0001), although all the mice eventually died of leukemia. Nonetheless, as was detected in vitro, Ezh2δ/δ AML cells in BM were apparently differentiated in morphology compared with the control. Ezh2δ/δ AML cells in BM gave rise to 10-fold fewer colonies in methylcellulose medium compared with Ezh2+/+ AML cells, and again showed an obvious tendency of differentiation. These observations imply that Ezh2 is critical for the progression of MLL-AF9 AML and maintains the immature state of AML cells. To elucidate the mechanism how Ezh2 promotes the progression of MLL-AF9-induced AML, we examined the genome-wide distribution of tri-methylation of histone H3 at lysine 27 (H3K27me3) by ChIP-sequencing and microarray-based expression analysis. ChIP-sequencing using Ezh2+/+ and Ezh2δ/δ BM AML cells identified 3525 and 89 genes exhibiting a ≧ 10-fold enrichment in H3K27me3 levels in Ezh2+/+ and Ezh2δ/δ AML cells, respectively, confirming a drastic reduction in the levels of global H3K27me3 in the absence of Ezh2. Microarray analysis using lineage marker (except for Mac1)−Sca-1−c-Kit+FcγRII/IIIhi BM AML cells revealed 252 upregulated and 154 downregulated genes (≧ 2-fold) in Ezh2δ/δ AML cells compared with Ezh2+/+ AML cells. Of interest, the absence of Ezh2 did not affect the transcriptional activation of the major target genes of MLL-AF9, including HoxA9 and Meis1. Because Ezh2 functions as transcriptional repressor, de-repressed genes could be direct targets of Ezh2. Based on these data, we are now engaged in further comprehensive analysis to narrow down the direct target genes of Ezh2 responsible for the progression of AML. Collectively, our findings suggest that Ezh2 is the major enzyme for H3K27me3 in AML and contributes to the progression of AML by regulating transcription a cohort of genes that are supposedly relevant to the self-renewal capacity and perturbed differentiation of AML stem cells. Disclosures: No relevant conflicts of interest to declare.
Dissertations / Theses on the topic "EZH2i"
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Cannito, Sara. "Modeling of cancer immune phenotype by new epigenetic drugs: a strategy to improve efficacy of immunotherapy." Doctoral thesis, Università di Siena, 2020. http://hdl.handle.net/11365/1120775.
Full textAbstract:
Il mesotelioma pleurico maligno (MPM) è un tumore molto aggressivo e rapidamente progressivo che si sviluppa a livello del mesotelio che compone la pleura; questa neoplasia può assumere diversi sottotipi istologici (epitelioide, bifasico e sarcomatoide), i quali sono strettamente correlati alla prognosi. Le modificazioni epigenetiche che avvengono nelle fasi di iniziazione e progressione del MPM possono svolgere un ruolo fondamentale nel regolare negativamente il crosstalk tra tumore e sistema immunitario, contribuendo a mantenere un microambiente tumorale immunosoppressivo. Conoscere più dettagliatamente il panorama epigenetico del MPM può contribuire a definire il razionale per nuove terapie antitumorali e porre le basi per studi di combinazione che prevedano l’utilizzo di farmaci epigenetici con farmaci immunoterapeutici.
Con il presente studio abbiamo voluto valutare, in un primo momento, le modificazioni nel profilo di espressione genica di 10 linee di MPM, di diverso istotipo, trattate con la guadecitabina, un agente demetilante il DNA di seconda generazione, tramite la piattaforma nCounter di Nanostring. I risultati ottenuti tramite Ingenuity Pathway Analysis (IPA) hanno mostrato che la guadecitabina era in grado di indurre l’attivazione dei geni coinvolti nel crosstalk tra cellule dendritiche e natural killer nel 50% delle linee cellulari di MPM indagate, accompagnata dall’attivazione di altre componenti coinvolte nella risposta immunitaria a infezioni e infiammazioni. I fattori trascrizionali “upstream” più frequentemente attivati appartenevano al pathway di segnalazione dell’interferon (IFN)-γ. Inoltre, è stata riscontrata l’up-regolazione (fold change medio (mFC) ≥ 1.5) di molecole immuno-relate, come NY-ESO-1 (mFC=13.16), MAGE-B2 (mFC=13.09), CD70 (mFC=5.27) e CTLA-4 (mFC=4.81).
Abbiamo inoltre effettuato analisi istotipo-specifiche per esplorare le modificazioni molecolari indotte dalla guadecitabina nei 3 sottotipi di MPM. La guadecitabina ha indotto l’up-regolazione dell’espressione di marcatori del fenotipo epiteliale (es. CDH1, EPCAM e PECAM1), osservata ad alti livelli nelle linee cellulari sarcomatoidi; ciò è stato associato alla down-regolazione di molecole di origine mesenchimale (es. CDH2 e NCAM) e induttori della cascata metastatica (es. CDH11).
Successivamente abbiamo comparato gli effetti immunomodulatori della guadecitabina con quelli di altri farmaci epigenetici (gli inibitori delle iston acetiltransferasi (HDAC) VPA e SAHA o l’inibitore di EZH2 EPZ-6438) da soli o in combinazione con la guadecitabina in 5 linee cellulari di MPM (2 sarcomatoidi, 1 bifasica e 2 epitelioidi). Analisi citofluorimetriche e molecolari hanno rivelato che la guadecitabina up-regolava l’espressione delle molecole immuno-relate, quali HLA di classe I (mFC=1.59), ICAM-1 (mFC=3.27), PD-L1 (mFC=2.13), e NKG2DL (MICA mFC=1.88, MICB mFC=2.42, ULBP2 mFC=3.16), inducendo/up-regolando l’espressione dei Cancer Testit Antigens (CTA) NY-ESO-1, MAGE-A1 e MAGE-A3; il VPA up-regolava l’espressione degli antigeni di HLA di classe I (mFC=1.50), PD-L1 (mFC=2.76), NKG2DL (MICA mFC=1.69, MICB mFC=2.67, ULBP2 mFC=3.26) e quella dei CTA MAGE-A1 e MAGE-A3, rispettivamente in 2/5 e 3/5 linee cellulari di MPM; il SAHA up-regolava l’espressione di MICA (mFC=1.57), MICB (mFC=4.05) e MAGE-A1 e MAGE-A3, rispettivamente in 2/5 e 4/5 linee cellulari; per contro, l’EPZ-6438 ha mostrato minime capacità immunomodulanti, inducendo solamente NY-ESO-1 e up-regolando l’espressione di PD-L1, MICB e ULBP2 in 1 linea cellulare ciascuno. Contrariamente ai risultati eterogenei ottenuti dai singoli farmaci, l’associazione di VPA, SAHA o EPZ-6438 alla guadecitabine ha rafforzato le capacità immunomodulanti di quest’ultima, influenzando l’espressione di tutte le molecole indagate. Specificatamente, le combinazioni di guadecitabine con VPA, SAHA o EPZ-6438 up-regolavano l’espressione degli antigeni HLA di classe I (mFC=2.21, 2.03, o 2.29 rispettivamente), di ICAM-1 (mFC=4.09, 4.63, o 5.33), di PD-L1 (mFC=6.95, 2.42, o 2.50), di MIC-A (mFC=3.48, 2.00, o 2.23), di MIC-B (mFC=6.80, 2.48, o 2.81) e di ULBP2 (mFC=13.45, 3.40, o 4.11). Infine, livelli di up- regolazione/induzione maggiori sono stati osservati per i CTA a seguito di tutti e 3 i trattamenti combinati rispetto alla guadecitabina in singolo. La modulazione delle caderine è stata influenzata dal sottotipo istologico di MPM: l’espressione di CDH1 è stata indotta dalla guadecitabina in singolo e dalla sua combinazione con VPA, SAHA e EPZ-6438 nelle 2 linee cellulari sarcomatoidi, costitutivamente negative per l’espressione del gene; l’espressione di CDH2 è stata up-regolata dal VPA e dal SAHA singoli in 1/5 linee cellulari e dalle combinazioni di guadecitabina con VPA o SAHA, rispettivamente in 3/5 o 1/5 linee cellulari di MPM; ciononostante, non è stata osservata alcuna up-regolazione del gene nelle 2 linee cellulari epiteliodi, costitutivamente negative per l’espressione di CDH2.
In conclusione, dalle analisi approfondite del pannello di espressione genica abbiamo confermato che la guadecitabina è in grado di up-regolare/indurre l’espressione di molecole immunitarie e immuno- relate cruciali per il crosstalk tra il tumore e il sistema immunitario; inoltre, abbiamo dimostrato che essa induce l’attivazione di geni correlati all’IFN, soprattutto nel fenotipo sarcomatoide, supportando l’ipotesi che i demetilanti possano aumentare la risposta immunitaria contro il MPM, potenzialmente anche del tipo istologico più aggressivo; la modulazione delle molecole di adesione tendente verso il fenotipo epitelioide suggerisce la possibilità di revertire la transizione epitelio-mesenchima, cruciale nel processo di metastatizzazione. Infine, combinando la guadecitabina con farmaci inibitori delle HDAC/EZH2 ha rafforzato la sua attività immunomodulante, fornendo il razionale per studi di associazione di farmaci epigenetici e agenti immunoterapici in modo da aumentare l’efficacia di questi ultimi nel trattamento del mesotelioma.Malignant pleural mesothelioma (MPM) is a highly aggressive and rapidly progressive tumor that affect the mesothelium componing the pleura; it can acquire different histological subtypes (mainly epithelioid, biphasic, and sarcomatoid MPM), which are of prognostic significance. Epigenetic modifications occurring during MPM initiation and progression may play a relevant role in negatively regulating the crosstalk between the tumor and the immune system, as well as contributing to the highly immunosuppressive microenvironment. A better understanding of MPM epigenetics will contribute to refine antitumor strategies, laying the ground for epigenetic-based immunotherapy. The present study evaluated, in the first instance, changes in the gene expression fingerprint of 10 MPM cell lines of different phenotype treated with the second-generation DNA hypomethylating agent (DHA) guadecitabine, through the Nanostring Oncology panel with nCounter readout. Ingenuity pathway analysis results revealed that guadecitabine induced the activation of natural killer and dendritic cells signaling pathways in 50% of MPM cell lines, followed by the activation of other components involved in the immune system response to infections and inflammation. Besides, the most frequently activated upstream regulators belonging to the interferon (IFN)-γ signaling pathway. Also, the up- regulation (mean fold change (mFC) ≥ 1.5) of key immune-related molecules, such as the NY-ESO-1 (mFC=13.16), MAGE-B2 (mFC=13.09), CD70 (mFC=5.27), and CTLA-4 (mFC=4.81) was reported. We also performed histological type-specific investigations to explore molecular changes induced by guadecitabine among the 3 histotypes. Guadecitabine induced the up-regulation of the expression of epithelial markers (e.g., CDH1, EPCAM, PECAM1), observed at higher levels in sarcomatoid cell lines; this was accompanied by the down-regulation of mesenchymal origin molecules (e.g., CDH2, NCAM), and inductor of metastatic signals (e.g., CDH11). Secondly, the immunomodulatory effects of guadecitabine were compared to those of different epigenetic drugs (the histone deacetylase (HDAC) inhibitors VPA and SAHA, or the EZH2 EPZ- 6438), alone or in combination with guadecitabine, in 5 MPM cell lines (two sarcomatoid, one biphasic, and two epithelioid). We performed cytofluorimetric and molecular qRT-PCR analyses and, in this regard, results showed that guadecitabine up-regulated the expression of immune-related molecules, such as HLA class I antigens (mFC=1.59), ICAM-1 (mFC=3.27), PD-L1 (mFC=2.13), and NKG2DLs (MIC-A mFC=1.88, MIC-B mFC=2.42, and ULBP2 mFC=3.16), and up-regulated/induced Cancer Testis Antigens (CTA: NY-ESO-1, MAGE-A1, and MAGE-A3) expression; VPA up-regulated the expression of HLA class I antigens (mFC=1.50), PD-L1 (mFC=2.76), NKG2DLs (MIC-A mFC=1.69, MIC-B mFC=2.67, and ULBP2 mFC=3.26), and the expression of CTA MAGE-A1 and MAGE-A3 in 2/5 and 3/5 MPM cell lines, respectively; SAHA up- regulated the expression of MICA (mFC=1.57), MICB (mFC=4.05), MAGE-A1 and MAGE-A3 in 2/5and 4/5 MPM cell lines, respectively; conversely, EPZ-6438 induced minimal immunomodulatory effects, inducing only NY-ESO-1 and up-regulating PD-L1, MIC-B, and ULBP2 expression in 1 MPM cell line each. Despite the heterogeneous activities of single epigenetic drugs, the addition of both VPA, SAHA, and EPZ-6438 to guadecitabine strengthened the immunomodulatory effects of the latter, by affecting the expression of all investigated molecules. Specifically, guadecitabine plus VPA, SAHA, or EPZ-6438 upregulated the expression of HLA class I antigens mFC=2.21, 2.03, or 2.29; ICAM-1 mFC=4.09, 4.63, or 5.33; PD-L1 mFC=6.95, 2.42, or 2.50; MIC-A mFC=3.48, 2.00, or 2.23; MIC-B mFC=6.80, 2.48, or 2.81; ULBP2 mFC=13.45, 3.40, or 4.11, respectively. Lastly, higher levels of upregulated/induced CTA expression were observed after all 3 combination treatments versus guadecitabine alone. Cadherins modulation was MPM histotype-related: CDH1 expression was induced in the 2 constitutive-negative sarcomatoid MPM cell lines by guadecitabine alone or combined with VPA, SAHA, or EPZ-6438; CDH2 expression was upregulated by VPA or SAHA in 1/5 cell lines, and by guadecitabine plus VPA or SAHA in 3/5 or in 1/5 MPM cell lines, respectively; however, no induction of CDH2 have been reported in the constitutive negative epithelioid cell lines. Overall, from comprehensive gene expression panel analyses, we confirmed that guadecitabine induced/up-regulated the expression of immune and immune-related molecules, pivotal in the tumor- immune system crosstalk; also, we highlighted that guadecitabine-induced activation of IFN-related genes, especially in the sarcomatoid phenotype, supporting the hypothesis that DHA could increase the immune response against MPM, potentially also with sarcomatoid features; moreover, the modulation of adhesion molecules towards the epithelial type suggests the possibility to revert the epithelial-to- mesenchymal transition (EMT) event, crucial in the invasion-metastasis cascade. Also, combining guadecitabine with HDACi/EZH2i strengthened its immunomodulatory capabilities, laying the rationale for epigenetic drugs-based immunotherapies, to enhance efficacy of these strategy in the MPM clinic.
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Shinde, Sneha. "Role of EZH2 in myelodysplastic syndromes." Thesis, King's College London (University of London), 2015. https://kclpure.kcl.ac.uk/portal/en/theses/role-of-ezh2-in-myelodysplastic-syndromes(323849bf-af95-47e6-8b6d-3393585bfe87).html.
Full textAbstract:
Occurrence of mutations in the Polycomb (PcG) gene; EZH2 (Enhancer of Zeste Homologue 2) represent a new class of molecular lesions associated with instability in the epigenome of patients with Myelodysplastic Syndrome (MDS). Detection of microdeletion at 7q36.1 or 7q Copy Neutral Loss of Heterozygosity [CN (LOH)] led to the identification of EZH2 mutations. EZH2 is the catalytic component of Polycomb Repressive Complex 2 (PRC2) that trimethylates lysine 27 of histone 3 (H3K27) resulting in gene silencing and recruitment of the sister complex i.e. Polycomb Repressive Complex 1 (PRC1) to target genes. Discovery of EZH2 mutations have shed light on the involvement of other PcG and PcG interacting proteins i.e. Jumonji (jmj) family of demethylases and DNA methyltrasferase 3A (DNMT3A) in MDS. Investigation of Single Nucleotide Polymorphism (SNP) array abnormalities and mutational analysis of these genes have not been ascertained and therefore I examined cytogenetic aberrations affecting twelve Polycomb (PRC1) and seventeen Jumonji genes using high density SNP 6 arrays. SNP6 data analyzed in this study was generated by our group for previous research projects. I visualised this data using CHromosome Analysis Suite (Chas) from Affymetrix and identified five PRC1 genes (BMI1, PHC1, PHC2, RING1A and RING1B) in 17/91 (19 %) patients with either Copy Number Variations (CNVs) like deletions or amplifications or CN (LOH). Interestingly, the frequency of SNP6 aberrations was high (two times) in Jumonji genes as compared to PRC1. 29/91 patients (31 %) showed either CNVs or CN (LOH) in fifteen (JMJD3, JMJD4, JMJD1B, JMJD2A, JARID2, JMJD1C, JARID1B, JMJD2C, UTX, JARID1C, JARID1A, JMJD2D, JHJD1A, JARID1D and JHJD1B) Jumonji genes. Mutational analysis of patients with SNP6 aberrations was carried out using Sanger or 454 sequencing but no mutations were detected in either the PRC1 or Jumonji genes. To elucidate changes in gene expression as a result of amplification or deletion of genomic material, qPCR was performed on 22/29 patients for thirteen Jumonji genes. Gene expression of JARID1A, JARID1C and UTX were modulated concomitant to the CNVs. Deletion of JARID1A locus was associated with reduced gene expression (p value < 0.0001) in two patients while trisomy of JARID1C (n=1) and UTX (n=2) were associated with increased expression (p value < 0.0001) of both the genes. Mutational analysis of PRC2 core components (SUZ12, EED, EZH1) and DNMT3A was carried out in a cohort of 61 MDS patients previously sequenced by our group for EZH2 mutations to examine their mutational overlap. 10/61 patients had heterozygous DNMT3A mutations (clone size 20-44 %) with two patients showing mutations at the R882 site. Interestingly, these mutations were seen predominantly (n= 6) in patients with monosomy 7/del 7q however only one patient had both DNMT3A (R882H) and EZH2 (V626M) mutations suggesting that there is no specific association between mutations of the two genes. In contrast, PRC2 genes were not mutated in this cohort emphasizing the importance of EZH2 mutations alone in MDS pathogenesis. Therefore I examined the functional consequences of the commonly occurring EZH2 (R690C/R690H) and DNMT3A (R882H) mutations in myeloid cell lines. To achieve this, numerous attempts were made to clone DNMT3A R882H mutation into p3XFLAG-myc-CMV-26 to allow transfection and in vitro assessment of the mutant in myeloid cells but all attempts to ligate the plasmid failed and therefore work on DNMT3A was discontinued. EZH2 (R690C/R69H) and Flag tagged wild type EZH2 were constructed in p3XFLAGmyc- CMV-26 vector using a PCR based cloning strategy and transfected into K562 cells. Western blot analysis at 72 hr post transfection, showed elevated levels of both R690C/R690H mutants and Flag tagged wild type EZH2 but no alterations in its target H3K27me3 levels. Affymetrix Human Transcriptome 2.0 gene expression profiling was used to identify modulation of gene signature as result of elevated EZH2 levels and MLLT10 gene was found to be up regulated in cells transfected with Flag-tagged wild type EZH2 (2.3 fold) as well as R690C/ R690H (3.6 – 4.6 fold) mutants. In contrast, PML (promyelocytic leukaemia) (2.16 fold) and FANCL (Fanconi Anaemia, Complementation Group L) (2.18 fold) genes were up regulated exclusively in cells over expressing the Flag tagged wild type EZH2. To compare this gene signature to gene expression changes as a result of EZH2 knock out (KO), shRNA mediated inhibition of EZH2 was carried out in myeloid cells and 95 % KO of both EZH2 and H3K27me3 levels were observed at Day 7 post transduction. Microarray gene expression profiling identified BCL2 (-2.14 fold), FLT1 (-4.03 fold), HOXA10 (-2.2 fold), CD44 (-8.2 fold), CD83 (-2.1 fold), TLSP (-3.24 fold), IFI16 (-3.11 fold) and PAG1 (-3.37 fold) inhibition in cells transduced with shRNA against EZH2 compared to the scrambled and wild type K562 cells. There were no overlapping genes in K562 cells with EZH2 KO and EZH2 mutants R690C/R690H. The differences in expression profiling could be due to the difference in H3K27me3 levels modulated by EZH2. Comparison of gene signature obtained by EZH2 KO on patient samples carrying the R690H mutation, showed contrasting results i.e. up regulation of HOXA10, FLT1, PAG1B, EZH1 and TLSP compared to patients with wild type EZH2 suggesting that EZH2 R690C/R690H mutants do not mimic the transcriptional changes seen in EZH2 KO. This strongly suggests the presence of other mechanisms to compensate for the loss of EZH2 in myeloid cells. However the results obtained here should be examined in additional other myeloid cell lines to validate the findings obtained in K562 cells.
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Bachmann, Natascha. "Molekulargenetische Untersuchungen zum EZH2-Gen beim Prostatakarzinom." [S.l. : s.n.], 2006. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-56332.
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Patil, Shilpa [Verfasser]. "EZH2-GATA6 axis in Pancreatic ductal adenocarcinoma / Shilpa Patil." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2020. http://d-nb.info/1218780746/34.
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Booth, Christopher. "Collaboration of Ezh2 and Runx1 inactivating mutations in malignant haematopoiesis." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:3f3b18b1-5875-42ed-b025-cf0dd457b99f.
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Extensive efforts have shed light on the identity and biology of cancer stem cells, required and sufficient for the propagation of hematological malignancies and solid tumours. Much less is understood about the closely related issue as to the identity and properties of the normal stem and progenitor cells targeted by oncogenic lesions, and how the nature of the targeted cell might impact on the biology and clinical picture of the resulting cancer. To address this, we developed a mouse model allowing targeted inactivation of Ezh2 and Runx1 to different haematopoietic compartments. Inactivating mutations of EZH2 and RUNX1 frequently co-occur in haematological malignancies with markedly different phenotypes including myelodysplastic syndrome (MDS) and early thymic progenitor (ETP) leukaemia. Inactivation of Ezh2 and Runx1 in adult haematopoietic stem cells (HSCs) resulted in perturbed haematopoiesis leading to development of an MDS-like disease. Unexpectedly, this MDS phenotype could be fully reproduced when Ezh2 and Runx1 inactivation was targeted to multipotent progenitors (MPPs) using Flt3-Cre. Furthermore, the disease was transplantable by MPPs, but not more committed progenitor populations, demonstrating that MDS tumour propagating potential is not exclusive to intrinsically self-renewing HSCs. Targeting Ezh2 and Runx1 inactivation to early lympho-myeloid progenitors did not result in an MDS phenotype. These mice showed a marked expansion of ETPs within the thymus, combined with a block in thymocyte differentiation. These expanded ETPs displayed transcriptional features characteristic of ETP leukaemia, a treatment-resistant acute leukaemia subtype hypothesised to originate from ETPs. Combination of inactivation of Ezh2 and Runx1 in ETPs with the constitutively activating Flt3-ITD signalling mutation resulted in an aggressive lympho-myeloid acute leukaemia, which could be propagated by the expanded ETP population. These findings demonstrate the potential of lympho-myeloid progenitors such as ETPs to become leukaemia stem cells which propagate a disease retaining lympho-myeloid features. We used this novel ETP leukaemia model to explore therapeutic targeting of Ezh2-inactivated ETP leukaemias using inhibitors of the bromodomain and extra terminal (BET) proteins. Aberrant transcription resulting from epigenetic changes induced by Ezh2 loss could be reversed by BET inhibitors, and these compounds showed therapeutic efficacy against both mouse and human ETP leukaemias in vitro and in vivo.
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Woodhouse, Samuel. "The role of Ezh2 in adult muscle stem cell fate." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610201.
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Thulabandu, Venkata Revanth Sai Kumar. "REGULATION OF CELLULAR DIFFERENTIATION BY EZH2 DURING SKIN ANDMUSCLE DEVELOPMENT." Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1623415890187889.
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Rachow, Laura-Louise [Verfasser], Elmar [Akademischer Betreuer] Stickeler, and Martin [Akademischer Betreuer] Werner. "Die Bedeutung der molekularen Marker EZH2 und SNCG beim Endometriumkarzinom." Freiburg : Universität, 2020. http://d-nb.info/1216038570/34.
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Tabbal, Houda. "Mécanismes moléculaires régulés par la méthyltransférase EZH2 dans les corticosurrénalomes." Thesis, Université Clermont Auvergne (2017-2020), 2018. http://www.theses.fr/2018CLFAC081/document.
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Les cortico-surrénalomes (CCS) sont considérés comme des tumeurs malignes endocriniennes rares, associées à un pronostic sombre. Les trois mécanismes moléculaires les plus fréquemment altérés dans les CCS comprennent les mutations inactivatrices du gène suppresseur de tumeur TP53,la surexpression de IGF-II et l'activation constitutive de la voie de signalisation Wnt/β-caténine. En utilisant des modèles de souris transgéniques, nous avons montré que ces altérations, même combinées, ne sont pas suffisantes pour permettre la progression maligne.Nous avons précédemment identifié l'histone méthyltransférase EZH2 comme le modificateur d'histone le plus dérégulé dans les CCS. Nous avons également montré que sa surexpression est associée à une progression tumorale et à un mauvais pronostic. Cependant, les mécanismes sous-jacents de cette agressivité sont largement inconnus. Dans cette étude, nous avons cherché à identifier les gènes cibles de EZH2 dans les CCS, qui sont soient activés, soient réprimés. Ainsi, nous avons effectué une analyse bio-informatique des données du transcriptome de trois cohortes de patients porteurs de CCS. L’analyse montre une forte corrélation entre la surexpression de EZH2 et les gènes régulés positivement, suggérant un rôle majeur d’inducteur transcriptionnel de EZH2 dans les CCS. Nous avons montré que cette activité positive repose sur une interaction entre EZH2 et E2F1, qui entraîne la surexpression de gènes impliqués dans la régulation du cycle cellulaire et la mitose tels que RRM2,PTTG1 et PRC1/ASE1. Nous avons montré que l'inhibition de RRM2 par ARN interférent ou traitement pharmacologique avec le GW8510 inhibe la croissance cellulaire, la capacité à combler les blessures, la croissance clonogénique, la migration et induit l'apoptose des cellules H295R en culture. En revanche, l'expression du facteur pro-apoptotique NOV/CCN3 est diminuée dans les CCS, ce qui est corrélé au développement de tumeurs agressives. Nos analyses moléculaires montrent que l'inhibition de EZH2 augmente l'expression de NOV/CCN3, suggérant que la surexpression de EZH2 pourrait favoriser la progression maligne des CCS en inhibant les stimulateurs de l'apoptose. Le facteur NOV a déjà été identifié comme cible négative du récepteur nucléaire SF1 dans les cellules du CCS, bien que les mécanismes moléculaires à l'origine de cette inhibition n'aient pas été identifiés. De manière intéressante, dans le cancer de la prostate, l'expression de NOV est inhibée par le récepteur des androgènes AR, grâce au recrutement de EZH2 qui pose la marque répressive H3K27me3. Nous avons pu identifier une coopération similaire entre SF1 et EZH2 pour réprimer l'expression de NOV et bloquer ainsi l'apoptose dans les CCS.Au total, ces résultats identifient SF1 et E2F1 comme deux partenaires indépendants de EZH2, induisant la répression de facteurs pro-apoptotiques et l'activation des gènes du cycle cellulaire respectivement, conduisant ainsi à l'agressivité des CCSAdrenocortical carcinomas (ACC) are regarded as rare endocrinemalignancies associated with dismal prognosis. The three common molecularmechanisms predominantly altered in ACC include inactivating mutations of theTP53 tumor suppressor gene, overexpression of IGF-II and constitutive activationof the Wnt/β-catenin signaling pathway. Using transgenic mouse models, wehave shown that these alterations, even when combined together, were notsufficient to induce malignant progression.We previously identified the histone methyltransferase EZH2 as the mostderegulated histone modifier in ACC. We have also shown that its overexpressionis associated with tumor progression and poor prognosis. Yet, the mechanismsunderlying this aggressiveness are largely unknown. Here, we aimed to identifyEZH2 target genes in ACC, which are either activated or repressed.Thus, we conducted a bio-informatics analysis of transcriptome data fromthree cohorts of ACC patients. The analysis showed a strong correlation betweenhighly expressed EZH2 and positively regulated genes suggesting a major role of‘transcriptional inducer‘ for EZH2 in ACC. We have shown that this positiveactivity relies on an interaction between EZH2 and E2F1 that results in theupregulation of genes implicated in cell cycle regulation and mitosis such asRRM2, PTTG1 and PRC1/ASE1. We showed that Inhibition of RRM2 by RNAinterference or pharmacological treatment with GW8510 inhibits cellular growth,wound healing, clonogenic growth, migration and induces apoptosis of H295Rcells in culture.In contrast, expression of the pro-apoptotic factor NOV/CCN3 is decreasedin ACC, which is correlated with development of aggressive tumours. Ourmolecular analyses show that EZH2 inhibition increases expression ofNOV/CCN3, suggesting that EZH2 overexpression may also favour malignantprogression in ACC by inhibition of apoptosis stimulators. NOV has previouslybeen identified as a negative target of the nuclear receptor SF1 in ACC cells,although the molecular mechanisms underlying this inhibition were unidentified.Interestingly, in prostate cancer, NOV expression is inhibited by the androgenreceptor, through recruitment of EZH2 and deposition of the H3K27me3 mark.We have been able to identify a similar cooperation between SF1 and EZH2 tosuppress NOV expression and block apoptosis in ACC.Altogether, these findings identifiy SF1 and E2F1 as two independentpartners of EZH2, inducing repression of proapoptotic factors, and activation ofcell cycle genes respectively, thus leading to aggressiveness of ACC
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Emhamed, Hasna [Verfasser], and Elmar [Akademischer Betreuer] Stickeler. "Potential functional implications of factors EZH2,NSSR1,and ZEB1 in endometrial carcinogenesis = Potenzielle funktionelle Implikationen von Faktoren EZH2, NSSR1 und ZEB1 in der endometrialen Karzinogenese." Freiburg : Universität, 2015. http://d-nb.info/1114996130/34.
Full textBooks on the topic "EZH2i"
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I, Kalinina S., Mikhiev A. I, Kholopt͡s︡eva N. P, and Institut biologii (Akademii͡a︡ nauk SSSR. Karelʹskiĭ filial), eds. Rekomendat͡s︡ii po vozdelyvanii͡u︡ ezhi sbornoĭ sorta Petrozavodskai͡a︡. Petrozavodsk: Karelʹskiĭ filial AN SSSR, 1986.
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Stepanova, Polina. Teatr bez kulis: Teatralʹnye opyty Ezhi Grotovskogo. Sankt-Peterburg: GIPERION, 2008.
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Tumanin, V. E. "Historia - moje życie": Nauchnoe nasledie Ezhi Topolʹskogo. Kazanʹ: Institut istorii AN RT, 2008.
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V, Markov A. Morskie ezhi semeĭstva Paleopneustidae (Echinoidea, Spatangoida): Morfologii︠a︡, sistema, filogenii︠a︡. Moskva: GEOS, 2001.
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Tembotova, F. A. Ezhi Kavkaza: Opyt izuchenii͡a︡ trekhmernoĭ izmenchivosti i adaptat͡s︡iĭ biologicheskogo obʺekta v gorakh. Nalʹchik: Izd-vo Kabardino-Balkarskogo nauch. t͡s︡entra RAN, 1997.
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Mnich, Roman, Justyna Urban, Roman Bobryk, and Jerzy Faryno. "Obraz mira, v slove i︠a︡vlennyĭ--": Sbornik v chestʹ 70-letii︠a︡ professora Ezhi Faryno. Siedlce: Instytut Filologii Polskiej i Lingwistyki Stosowanej Uniwersytetu Przyrodniczo-Humanistycznego w Siedlcach, 2011.
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K, Nikulin S., and Pichkhadze L. A, eds. Iskusstvo rezhissury, XX vek: K.S. Stanislavskiĭ, Vs.Meĭerkholʹd, Dzhordzho Streler, Ezhi Grotovskiĭ, Piter Bruk. Moskva: Artist. Rezhisser. Teatr, 2008.
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Shang sheng, bu ke e zhi: Yi ge xin hua she ji zhe er shi nian de jian zheng = Shangsheng, buke ezhi. Nanning Shi: Guangxi ren min chu ban she, 2006.
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Zong he fang zhi: E zhi fu bai fan zui de she hui gong cheng = Zonghe fangzhi : ezhi fubai fanzui de shehui gongcheng. Beijing Shi: Zhongguo fang zheng chu ban she, 2011.
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E zhi fu bai fan zui xin si wei: Gou jian yi zhi du fang fu yu yi fa fang fu wei ji dian de guo jia lian zheng jian she xin ti xi = Ezhi Fubai Fanzui Xinsiwei. Beijing: Zhongguo fa zhi chu ban she, 2013.
Find full textBook chapters on the topic "EZH2i"
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Au, Sandy Leung-Kuen, Irene Oi-Lin Ng, and Chun-Ming Wong. "Epigenetic Regulation of EZH2 and Its Targeted MicroRNAs." In Epigenetics and Cancer, 33–61. Dordrecht: Springer Netherlands, 2013. http://dx.doi.org/10.1007/978-94-007-6612-9_3.
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Kumar, Sanjay, James A. Stokes, Udai P. Singh, Kumar S. Bishnupuri, and Manoj K. Mishra. "Enhancer of Zeste Homology 2 (Ezh2), an Epigenetic Regulator: A Possibility for Prostate Cancer Treatment." In Epigenetic Advancements in Cancer, 229–44. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-24951-3_10.
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Qazi, Aamer M., Sita Aggarwal, Christopher S. Steffer, David L. Bouwman, Donald W. Weaver, Scott A. Gruber, and Ramesh B. Batchu. "Laser Capture Microdissection of Pancreatic Ductal Adeno-Carcinoma Cells to Analyze EzH2 by Western Blot Analysis." In Methods in Molecular Biology, 245–56. Totowa, NJ: Humana Press, 2011. http://dx.doi.org/10.1007/978-1-61779-163-5_20.
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"Ezhai Formation." In Geological Formation Names of China (1866–2000), 278. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-540-93824-8_1969.
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"EZH2 Mutation." In Diagnostic Pathology: Molecular Oncology, 3–60. Elsevier, 2016. http://dx.doi.org/10.1016/b978-0-323-37678-5.50038-4.
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Lindsay, Cameron, Morris Kostiuk, and Vincent L. Biron. "Pharmacoepigenetics of EZH2 Inhibitors." In Pharmacoepigenetics, 447–62. Elsevier, 2019. http://dx.doi.org/10.1016/b978-0-12-813939-4.00009-7.
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Noodin, Margaret. "Ezhi-enendamang Anishina abebiigeng:." In Papers of the Forty-Ninth Algonquian Conference, 183–200. Michigan State University Press, 2020. http://dx.doi.org/10.14321/j.ctvv417gp.15.
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Weaver, David D. "Weaver Syndrome and EZH2-Related Overgrowth Syndromes." In Overgrowth Syndromes, 95–126. Oxford University Press, 2019. http://dx.doi.org/10.1093/med/9780190944896.003.0005.
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Comprehensive details on Weaver syndrome, one of the best recognized of the overgrowth syndromes, are presented in this chapter. The syndrome is characterized by overgrowth of prenatal onset, a distinctive craniofacial appearance, camptodactyly, widened metaphysis, accelerated bone age, and developmental delay. Like other overgrowth syndromes, Weaver syndrome is accompanied by an increased risk of malignancies, neuroblastoma, leukemia, and lymphoma in particular. The diagnosis relied on clinical evaluation alone until 2012 when the causative gene, EZH2, was discovered. The gene product joins with other related proteins to form a polycomb repressive complex that functions as an epigenetic signal that compacts chromatin and silences genes by histone modifications.
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Noodin, Margaret A. "6. Ezhi-gikendamang Aanikanootamang Anishinaabemowin: Anishinaabe Translation Studies." In At Translation's Edge, 123–35. Rutgers University Press, 2019. http://dx.doi.org/10.36019/9781978803374-007.
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Bendari, Mounia, and Nisrine Khoubila. "Cytogenetic and Genetic Advances in Myelodysplasia Syndromes." In Cytogenetics - Classical and Molecular Strategies for Analysing Heredity Material. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.97112.
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Myelodysplasia syndromes (MDS) are defined by a heterogeneous group of myeloid malignancies characterized by peripheral blood cytopenia and dishematopoiesis and frequently progress to acute myeloid leukemia. Conventional karyotype has a crucial role in myelodysplastic syndrome (MDS) and is one of items of the International Prognostic Scoring System (IPSS) for patient risk stratification and treatment selection. Approximately 50–60% of cases of MDS present chromosomal abnormalities, like the deletions of chromosome 5q and 7q, trisomy 8, and complex karyotypes. New genomic technologies have been developted, like single-nucleotide polymorphism array and next-generation sequencing. They can identify the heterozygous deletions wich result in haplo-insufficient gene expression (e.g., CSNK1A1, DDX41 on chromosome 5, CUX1, LUC7L2, EZH2 on chromosome 7) involved in the pathogenesis of myelodysplasia syndromes. Genetic abnormalities are multiple, the most recurrent one are involved in the RNA splicing like SF3B1, SRSF2, U2AF1, ZRSR2, LUC7L2, and DDX41. Epigenetic modifications are also identified, such as histone modification as ASXL1, EZH2. Finally, it can be DNA methylation (e.g., TET2, DNMT3A, IDH1/IDH2). On this review we will summarize the most recent progress in molecular pathogenesis of MDS, and try to better understand the pathogenesis of the specific subgroups of MDS patients and applications of discovery of new genetic mutation in the development of new therapeutic.
Conference papers on the topic "EZH2i"
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Watanabe, Marina, Rysn Kuzmickas, and Karen Cichowski. "Abstract P1-18-27: Developing a novel combination therapy using EZH2i for HER2+ breast cancer." In Abstracts: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.sabcs19-p1-18-27.
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Arora, Shilpi, Kaylyn Williamson, Srividya Balasubramanian, Jennifer Busby, Shivani Garapaty-Rao, Charlie Hatton, Dhanalakshmi Sivanandhan, Barbara Bryant, Emmanuel Normant, and Patrick Trojer. "Abstract PR09: EZH2 inhibitors reveal broad EZH2 dependencies in multiple myeloma." In Abstracts: AACR Special Conference: Chromatin and Epigenetics in Cancer; September 24-27, 2015; Atlanta, GA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.chromepi15-pr09.
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Kim, Woojin, Gregory H. Bird, Tobias Neff, Guoji Guo, Marc A. Kerenyi, Loren D. Walensky, and Stuart H. Orkin. "Abstract B254: Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Oct 19-23, 2013; Boston, MA. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1535-7163.targ-13-b254.
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Creasy, Caretha L., Michael T. McCabe, Susan Korenchuk, Elsie Diaz, Heidi Ott, Christine S. Thompson, Gopi Ganji, et al. "Abstract 4700: A novel selective EZH2 inhibitor exhibits anti-tumor activity in lymphoma with EZH2 activating mutations." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-4700.
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Dhanak, Dashyant. "Abstract SY02-02: Inhibition of methyltransferase EZH2." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-sy02-02.
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Gonzalvez, Francois, Theresa Baker, Justin Pritchard, Victor M. Rivera, and Andrew Garner. "Abstract 3597: EZH2 D1 domain mutants confer acquired resistance to EZH2-targeted inhibitors and reprogram B-cell transcription." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-3597.
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Leitner, K., V. Wieser, I. Tsibulak, K. Knoll, J. Kögl, D. Reimer, C. Marth, H. Fiegl, and A. G. Zeimet. "Die Expression der Histon-Methyltransferase EZH2 beim Ovarialkarziom." In Kongressabstracts zur Wissenschaftlichen Tagung der Arbeitsgemeinschaft für gynäkologische Onkologie (AGO) der Österreichischen Gesellschaft für Gynäkologie und Geburtshilfe (OEGGG). Georg Thieme Verlag KG, 2020. http://dx.doi.org/10.1055/s-0039-3403392.
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Kim, Eunhee, Dong-Hun Woo, and Jeongwu Lee. "Abstract 5215: EZH2-mediated STAT3 activation in glioblastoma." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-5215.
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Puca, Loredana, Dong Gao, Myriam Kossai, Clarisse Marotz, Juan Miguel Mosquera, Theresa Y. MacDonald, Kyung Park, et al. "Abstract 3844: Targeting EZH2 in neuroendocrine prostate cancer." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-3844.
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Yomtoubian, Shira, Seongho Ryu, Sharrell Lee, Lauren Havel, Dingcheng Gao, and Vivek Mittal. "Abstract 4447: EZH2 contributes to breast cancer metastasis." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-4447.
Full textReports on the topic "EZH2i"
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Wu, Lily. Imaging Metastatic Prostate Cancer After Genetic Manipulation of Transcriptional Memory Regulators EZH2 and EED. Fort Belvoir, VA: Defense Technical Information Center, January 2005. http://dx.doi.org/10.21236/ada435799.
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Moore, Heather K., and Celina G. Kleer. Understanding the Function of EZH2 as a Determinant of Breast Cancer Invasion and Metastasis. Fort Belvoir, VA: Defense Technical Information Center, April 2013. http://dx.doi.org/10.21236/ada578212.
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Zhao, Zhou, Zhaolun Cai, Tianxiang Jiang, Xiaonan Yin, Bo Zhang, and Xiufeng Chen. Treatment-related adverse events of EZH2 inhibitor therapies in clinical trials: a systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, March 2023. http://dx.doi.org/10.37766/inplasy2023.3.0028.
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Review question / Objective: In this study, we used conventional Meta-analysis and Network meta-analysis (NMA) to evaluate the survival outcomes of best supportive care only and cytoreductive treatment before transplantation, survival outcomes of different disease states at transplantation, and the effects of each treatment on survival outcomes of MDS, respectively, with a view to comprehensive clinical treatment and individualized treatment of MDS patients before transplantation, providing evidence-based medical evidence, prolonging survival time and improving life quality. Information sources: We will search articles in three electronic database including PubMed, EMBASE and Cochrane Library. All the English publications until 2022 will be searched without any restriction of countries or article type. Reference list of all selected articles will independently screened to identify additional studies left out in the initial search.
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Mehra, Rohit. Tissue Microarray Assessment of Novel Prostate Cancer Biomarkers AMACR and EZH2 and Immunologic Response to Them in African-American and Caucasian Men. Fort Belvoir, VA: Defense Technical Information Center, April 2007. http://dx.doi.org/10.21236/ada470995.
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Meiri, Noam, Michael D. Denbow, and Cynthia J. Denbow. Epigenetic Adaptation: The Regulatory Mechanisms of Hypothalamic Plasticity that Determine Stress-Response Set Point. United States Department of Agriculture, November 2013. http://dx.doi.org/10.32747/2013.7593396.bard.
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Our hypothesis was that postnatal stress exposure or sensory input alters brain activity, which induces acetylation and/or methylation on lysine residues of histone 3 and alters methylation levels in the promoter regions of stress-related genes, ultimately resulting in long-lasting changes in the stress-response set point. Therefore, the objectives of the proposal were: 1. To identify the levels of total histone 3 acetylation and different levels of methylation on lysine 9 and/or 14 during both heat and feed stress and challenge. 2. To evaluate the methylation and acetylation levels of histone 3 lysine 9 and/or 14 at the Bdnfpromoter during both heat and feed stress and challenge. 3. To evaluate the levels of the relevant methyltransferases and transmethylases during infliction of stress. 4. To identify the specific localization of the cells which respond to both specific histone modification and the enzyme involved by applying each of the stressors in the hypothalamus. 5. To evaluate the physiological effects of antisense knockdown of Ezh2 on the stress responses. 6. To measure the level of CpG methylation in the promoter region of BDNF in thermal treatments and free-fed, 12-hour fasted, and re-fed chicks during post-natal day 3, which is the critical period for feed-control establishment, and 10 days later to evaluate longterm effects. 7. The phenotypic effect of antisense “knock down” of the transmethylaseDNMT 3a. Background: The growing demand for improvements in poultry production requires an understanding of the mechanisms governing stress responses. Two of the major stressors affecting animal welfare and hence, the poultry industry in both the U.S. and Israel, are feed intake and thermal responses. Recently, it has been shown that the regulation of energy intake and expenditure, including feed intake and thermal regulation, resides in the hypothalamus and develops during a critical post-hatch period. However, little is known about the regulatory steps involved. The hypothesis to be tested in this proposal is that epigenetic changes in the hypothalamus during post-hatch early development determine the stress-response set point for both feed and thermal stressors. The ambitious goals that were set for this proposal were met. It was established that both stressors i.e. feed and thermal stress, can be manipulated during the critical period of development at day 3 to induce resilience to stress later in life. Specifically it was established that unfavorable nutritional conditions during early developmental periods or heat exposure influences subsequent adaptability to those same stressful conditions. Furthermore it was demonstrated that epigenetic marks on the promoter of genes involved in stress memory are altered both during stress, and as a result, later in life. Specifically it was demonstrated that fasting and heat had an effect on methylation and acetylation of histone 3 at various lysine residues in the hypothalamus during exposure to stress on day 3 and during stress challenge on day 10. Furthermore, the enzymes that perform these modifications are altered both during stress conditioning and challenge. Finally, these modifications are both necessary and sufficient, since antisense "knockdown" of these enzymes affects histone modifications, and as a consequence stress resilience. DNA methylation was also demonstrated at the promoters of genes involved in heat stress regulation and long-term resilience. It should be noted that the only goal that we did not meet because of technical reasons was No. 7. In conclusion: The outcome of this research may provide information for the improvement of stress responses in high yield poultry breeds using epigenetic adaptation approaches during critical periods in the course of early development in order to improve animal welfare even under suboptimum environmental conditions.