TY - JOUR A1 - Sbirkov, Yordan A1 - Kwok, Colin A1 - Bhamra, Amandeep A1 - Thompson, Andrew J. A1 - Gil, Veronica A1 - Zelent, Arthur A1 - Petrie, Kevin T1 - Semi-quantitative mass spectrometry in AML cells identifies new non-genomic targets of the EZH2 methyltransferase JF - International Journal of Molecular Sciences N2 - Alterations to the gene encoding the EZH2 (KMT6A) methyltransferase, including both gain-of-function and loss-of-function, have been linked to a variety of haematological malignancies and solid tumours, suggesting a complex, context-dependent role of this methyltransferase. The successful implementation of molecularly targeted therapies against EZH2 requires a greater understanding of the potential mechanisms by which EZH2 contributes to cancer. One aspect of this effort is the mapping of EZH2 partner proteins and cellular targets. To this end we performed affinity-purification mass spectrometry in the FAB-M2 HL-60 acute myeloid leukaemia (AML) cell line before and after all-trans retinoic acid-induced differentiation. These studies identified new EZH2 interaction partners and potential non-histone substrates for EZH2-mediated methylation. Our results suggest that EZH2 is involved in the regulation of translation through interactions with a number of RNA binding proteins and by methylating key components of protein synthesis such as eEF1A1. Given that deregulated mRNA translation is a frequent feature of cancer and that eEF1A1 is highly expressed in many human tumours, these findings present new possibilities for the therapeutic targeting of EZH2 in AML. KW - acute myeloid leukaemia KW - EZH2 KW - mass spectrometry KW - methylation KW - eEF1A1 Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285541 SN - 1422-0067 VL - 18 IS - 7 ER - TY - JOUR A1 - Schümann, Franziska Lea A1 - Groß, Elisabeth A1 - Bauer, Marcus A1 - Rohde, Christian A1 - Sandmann, Sarah A1 - Terziev, Denis A1 - Müller, Lutz P. A1 - Posern, Guido A1 - Wienke, Andreas A1 - Fend, Falko A1 - Hansmann, Martin-Leo A1 - Klapper, Wolfram A1 - Rosenwald, Andreas A1 - Stein, Harald A1 - Dugas, Martin A1 - Müller-Tidow, Carsten A1 - Wickenhauser, Claudia A1 - Binder, Mascha A1 - Weber, Thomas T1 - Divergent effects of EZH1 and EZH2 protein expression on the prognosis of patients with T-cell lymphomas JF - Biomedicines N2 - T-cell lymphomas are highly heterogeneous and their prognosis is poor under the currently available therapies. Enhancers of zeste homologue 1 and 2 (EZH1/2) are histone H3 lysine-27 trimethyltransferases (H3K27me3). Despite the rapid development of new drugs inhibiting EZH2 and/or EZH1, the molecular interplay of these proteins and the impact on disease progression and prognosis of patients with T-cell lymphomas remains insufficiently understood. In this study, EZH1/2 mutation status was evaluated in 33 monomorphic epitheliotropic intestinal T-cell lymphomas by next generation sequencing and EZH1/2 and H3K27me3 protein expression levels were detected by immunohistochemistry in 46 T-cell lymphomas. Correlations with clinicopathologic features were analyzed and survival curves generated. No EZH1 mutations and one (3%) EZH2 missense mutation were identified. In univariable analysis, high EZH1 expression was associated with an improved overall survival (OS) and progression-free survival (PFS) whereas high EZH2 and H3K27me3 expression were associated with poorer OS and PFS. Multivariable analysis revealed EZH1 (hazard ratio (HR) = 0.183; 95% confidence interval (CI): 0.044–0.767; p = 0.020;) and EZH2 (HR = 8.245; 95% CI: 1.898–35.826; p = 0.005) to be independent, divergent prognostic markers for OS. In conclusion, EZH1/2 protein expression had opposing effects on the prognosis of T-cell lymphoma patients. KW - T-cell non-Hodgkin's lymphomas KW - PTCL KW - epigenetics KW - EZH1 KW - EZH2 KW - H3K27me3 KW - immunohistochemistry KW - next generation sequencing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252155 SN - 2227-9059 VL - 9 IS - 12 ER -