Clin Epigenetics. 2021 Apr 12;13(1):77. doi: 10.1186/s13148-021-01052-2.

Integrative study of EZH2 mutational status, copy number, protein expression and H3K27 trimethylation in AML/MDS patients.

Clinical epigenetics

Julia Stomper, Ruth Meier, Tobias Ma, Dietmar Pfeifer, Gabriele Ihorst, Nadja Blagitko-Dorfs, Gabriele Greve, Dennis Zimmer, Uwe Platzbecker, Anne Hagemeijer, Ingrid Schmitt-Graeff, Michael Lübbert

PMID: 33845873 PMCID: PMC8043064 DOI: 10.1186/s13148-021-01052-2

Abstract

BACKGROUND: Mutations in the EZH2 gene are recurrently found in patients with myeloid neoplasms and are associated with a poor prognosis. We aimed to characterize genetic and epigenetic alterations of EZH2 in 58 patients (51 with acute myeloid leukemia and 7 with myelodysplastic or myeloproliferative neoplasms) by integrating data on EZH2 mutational status, co-occurring mutations, and EZH2 copy number status with EZH2 protein expression, histone H3K27 trimethylation, and EZH2 promoter methylation.

RESULTS: EZH2 was mutated in 6/51 acute myeloid leukemia patients (12%) and 7/7 patients with other myeloid neoplasms. EZH2 mutations were not overrepresented in patients with chromosome 7q deletions or losses. In acute myeloid leukemia patients, EZH2 mutations frequently co-occurred with CEBPA (67%), ASXL1 (50%), TET2 and RAD21 mutations (33% each). In EZH2-mutated patients with myelodysplastic or myeloproliferative neoplasms, the most common co-mutations were in ASXL1 (100%), NRAS, RUNX1, and STAG2 (29% each). EZH2 mutations were associated with a significant decrease in EZH2 expression (p = 0.0002), which was similar in patients with chromosome 7 aberrations and patients with intact chromosome 7. An association between EZH2 protein expression and H3K27 trimethylation was observed in EZH2-unmutated patients (R

CONCLUSIONS: Perturbations of EZH2 activity in AML/MDS occur on different, genetic and non-genetic levels. Both low EZH2 protein expression and, by trend, EZH2 gene mutations predicted inferior overall survival of AML patients receiving standard chemotherapy.

Keywords: Acute myeloid leukemia; EZH2; H3K27 trimethylation; Mutations; Promoter methylation; Protein expression; Survival

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Publication Types

• Journal Article
• Research Support, Non-U.S. Gov't

Grant support

• SFB 992-C04/Deutsche Forschungsgemeinschaft
• FOR 2674/Deutsche Forschungsgemeinschaft
• Project ID L637/DKTK
• L660/DKTK