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Kempf, J.M.* ; Weser, S.* ; Bartoschek, M.D.* ; Metzeler, K.H.* ; Vick, B. ; Herold, T.* ; Völse, K. ; Mattes, R.* ; Scholz, M.* ; Wange, L.E.* ; Festini, M.* ; Ugur, E.* ; Roas, M.* ; Weigert, O.* ; Bultmann, S.* ; Leonhardt, H.* ; Schotta, G.* ; Hiddemann, W.* ; Jeremias, I. ; Spiekermann, K.*

Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML.

Sci. Rep. 11:5838 (2021)
Verlagsversion DOI
Open Access Gold
Creative Commons Lizenzvertrag
Chemotherapy resistance is the main impediment in the treatment of acute myeloid leukaemia (AML). Despite rapid advances, the various mechanisms inducing resistance development remain to be defined in detail. Here we report that loss-of-function mutations (LOF) in the histone methyltransferase EZH2 have the potential to confer resistance against the chemotherapeutic agent cytarabine. We identify seven distinct EZH2 mutations leading to loss of H3K27 trimethylation via multiple mechanisms. Analysis of matched diagnosis and relapse samples reveal a heterogenous regulation of EZH2 and a loss of EZH2 in 50% of patients. We confirm that loss of EZH2 induces resistance against cytarabine in the cell lines HEK293T and K562 as well as in a patient-derived xenograft model. Proteomics and transcriptomics analysis reveal that resistance is conferred by upregulation of multiple direct and indirect EZH2 target genes that are involved in apoptosis evasion, augmentation of proliferation and alteration of transmembrane transporter function. Our data indicate that loss of EZH2 results in upregulation of its target genes, providing the cell with a selective growth advantage, which mediates chemotherapy resistance.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 2045-2322
e-ISSN 2045-2322
Zeitschrift Scientific Reports
Quellenangaben Band: 11, Heft: 1, Seiten: , Artikelnummer: 5838 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Förderungen Physician Scientists Grant