Abstract
BackgroundMutations 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.ResultsEZH2 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).ConclusionsPerturbations 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.
Highlights
Mutations in the Enhancer of Zeste Homolog 2 (EZH2) gene are recurrently found in patients with myeloid neoplasms and are associ‐ ated with a poor prognosis
The EZH2 gene is located on chromosome 7q36.1, a region frequently deleted in Stomper et al Clin Epigenet (2021) 13:77 acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPN) [2]
Compared to the results of others looking at different AML subtypes in a much larger cohort of patients [25], we found that AML patients harboring EZH2 mutations were mostly older individuals and had a median of 4 mutations in genes associated with myeloid malignancies
Summary
Mutations in the EZH2 gene are recurrently found in patients with myeloid neoplasms and are associ‐ ated with a poor prognosis. In patients with MDS or MDS/ MPN, recurrent loss-of-function EZH2 mutations [6,7,8] are associated with a poor prognosis [9], and EZH2 is considered by many to act as a bona fide tumor suppressor gene [10, 11]. Regarding the transformation of MDS and MPN to AML, loss of EZH2 function appears to play an ambiguous role, being able to attenuate and promote leukemic transformation depending on the disease context and cooperating mutations [11, 13, 14]. Due to its complex function, far the mechanisms of action of proposed applications differ widely, ranging from preventing EZH2 degradation in order to overcome chemoresistance to inhibiting the PRC2 components EZH1 and -2 to reduce quiescent leukemia stem cells [4, 17]
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