Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML
Abstract 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 methyltransfer...
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Nature Portfolio
2021
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oai:doaj.org-article:0a2238e6e69947ba9113af2e76fa12bb2021-12-02T13:16:19ZLoss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML10.1038/s41598-021-84708-62045-2322https://doaj.org/article/0a2238e6e69947ba9113af2e76fa12bb2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84708-6https://doaj.org/toc/2045-2322Abstract 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.Julia M. KempfSabrina WeserMichael D. BartoschekKlaus H. MetzelerBinje VickTobias HeroldKerstin VölseRaphael MattesManuela ScholzLucas E. WangeMoreno FestiniEnes UgurMaike RoasOliver WeigertSebastian BultmannHeinrich LeonhardtGunnar SchottaWolfgang HiddemannIrmela JeremiasKarsten SpiekermannNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021) |
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Medicine R Science Q Julia M. Kempf Sabrina Weser Michael D. Bartoschek Klaus H. Metzeler Binje Vick Tobias Herold Kerstin Völse Raphael Mattes Manuela Scholz Lucas E. Wange Moreno Festini Enes Ugur Maike Roas Oliver Weigert Sebastian Bultmann Heinrich Leonhardt Gunnar Schotta Wolfgang Hiddemann Irmela Jeremias Karsten Spiekermann Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML |
| description |
Abstract 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. |
| format |
article |
| author |
Julia M. Kempf Sabrina Weser Michael D. Bartoschek Klaus H. Metzeler Binje Vick Tobias Herold Kerstin Völse Raphael Mattes Manuela Scholz Lucas E. Wange Moreno Festini Enes Ugur Maike Roas Oliver Weigert Sebastian Bultmann Heinrich Leonhardt Gunnar Schotta Wolfgang Hiddemann Irmela Jeremias Karsten Spiekermann |
| author_facet |
Julia M. Kempf Sabrina Weser Michael D. Bartoschek Klaus H. Metzeler Binje Vick Tobias Herold Kerstin Völse Raphael Mattes Manuela Scholz Lucas E. Wange Moreno Festini Enes Ugur Maike Roas Oliver Weigert Sebastian Bultmann Heinrich Leonhardt Gunnar Schotta Wolfgang Hiddemann Irmela Jeremias Karsten Spiekermann |
| author_sort |
Julia M. Kempf |
| title |
Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML |
| title_short |
Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML |
| title_full |
Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML |
| title_fullStr |
Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML |
| title_full_unstemmed |
Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML |
| title_sort |
loss-of-function mutations in the histone methyltransferase ezh2 promote chemotherapy resistance in aml |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/0a2238e6e69947ba9113af2e76fa12bb |
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