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

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 (R2 = 0.2, p = 0.01). The monoallelic state of EZH2 was not associated with EZH2 promoter hypermethylation. In multivariable analyses, EZH2 mutations were associated with a trend towards an increased risk of death (hazard ratio 2.51 [95% confidence interval 0.87–7.25], p = 0.09); similarly, low EZH2 expression was associated with elevated risk (hazard ratio 2.54 [95% confidence interval 1.07–6.04], p = 0.04). 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.

Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

“…Also, increased EZH2 expression was found in AML patients with complete remission when compared to newly diagnosed patients, who had no EZH2 mutations in either of the mutated hotspots [269]. Loss of EZH2 function can either attenuate and promote leukemic transformation in MDS and MPN, depending on the disease context and cooperating mutations [268].…”

“…In general, EZH2 mutations are associated with inferior overall survival in myeloid malignancies, with no increased rate of AML transformation in MDS patients [246,267]. In addition, decreased EZH2 expression is associated with worse overall survival in AML [268]. Also, increased EZH2 expression was found in AML patients with complete remission when compared to newly diagnosed patients, who had no EZH2 mutations in either of the mutated hotspots [269].…”

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

“…Vice versa, KDM2B overexpression rescues EZH2 expression in MDS cell lines by suppressing let-7b [ 18 ]. EZH2 functions as a tumor suppressor [ 66 , 67 ], clinically apparent by the poor prognosis of patients with AML/MDS with reduced EZH2 activity [ 68 , 69 ]. Andricovich et al likewise described an association between low expression of KDM2B and reduced survival of AML patients [ 19 , 70 , 71 ].…”

H3K9me3 represses G6PD expression to suppress the pentose phosphate pathway and ROS production to promote human mesothelioma growth

“…Epigenetic alteration of tumor-regulatory gene expression is a known mechanism of tumor growth control [ 54 ]. The histone methyltransferase inhibitor, verticillin A, has G9A inhibitory activity [ 23 ].…”