Association of <scp>EZH</scp>2 protein expression by immunohistochemistry in myelodysplasia related neoplasms with mutation status, cytogenetics and clinical outcomes

McGraw, Kathy L.; Nguyen, Jenny; Ali, Najla H Al; Komrokji, Rami; Sallman, David A.; Zhang, Xiaohui; Song, Jinming; Padron, Eric; Lancet, Jeffrey E.; Moscinski, Lynn C.; List, Alan F.; Zhang, Ling

doi:10.1111/bjh.15099

Cited by 6 publications

(9 citation statements)

References 7 publications

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“…Regarding the impact of altered EZH2 status on EZH2 protein expression, markedly reduced protein abundance was observed in patients with inactivating mutations and, to a lower extent, those with chromosomal loss of one copy of the gene. The reduced EZH2 protein expression in mutant compared to wild-type samples is in line with results published by McGraw et al [ 23 ]. However, in their cohort of myelodysplasia-related neoplasms, del(7q)/-7 lesions were overrepresented in EZH2 -mutated cases, resulting in a significantly lower EZH2 protein expression in del(7q)/-7 cases compared to cases with intact chromosome 7.…”

Section: Discussionsupporting

confidence: 91%

“…Thus, it is not surprising that for EZH2 —central in maintaining PRC2 activity—tumor suppressor function has been proposed when in 2010, inactivating point mutations in myeloid neoplasms were discovered by different groups [ 6 – 8 ]. Since then, the prevalence of EZH2 mutations, their association with deletions of the other allele, their pathogenic role [ 22 ], and negative clinical implications [ 9 , 23 ] have been broadly studied in MDS/MPN cohorts where alterations of this gene are relatively frequent and often associated with mutations in ASXL1 (also a member of the Polycomb group of proteins), TET2 , and RUNX1 [ 24 ]. In AML, EZH2 mutations have been reported with a prevalence of about 2% in more than 1500 patients comprehensively profiled for recurrent mutations [ 12 ], and to be highly specific for secondary AML [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

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

Stomper

Meier

et al. 2021

Clin Epigenet

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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

Stomper

Meier

et al. 2021

Clin Epigenet

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“…Regarding the evolution from MDS to AML, Mc Graw and colleagues suggested the EZH2 protein analysis by immunohistochemistry may be a molecular tool for discriminating disease outcome or transformation risk [20]. In our study, we also observed the importance of EZH2 expression results in MDS.…”

Section: Discussionsupporting

confidence: 77%

“…McGraw and colleagues studied EZH2 protein expression by immunohistochemistry in 33 MDS patients. It was observed that EZH2 expression was significant lower in −7 and del(7q) compared to those patients without these chromosomal alterations [20]. Xu and colleagues showed that the genomic loss of EZH2 [−7 and del(7q)] leads to low EZH2 expression in MDS and it is associated with shorter survival and increased AML transformation [21].…”

Section: Discussionmentioning

confidence: 99%

“…Based on these results, it is necessary new studies to clarify the signaling pathways in the three groups of EZH2 expression and studies involving a larger number of patients. Some studies have been reported the molecular pathways associated with EZH2 [10, 20, 25]. Xu and colleagues demonstrated that genomic loss of EZH2 contributes to overexpression of the HOX gene clusters in MDS by reducing H3K27me3 [21].…”

Section: Discussionmentioning

confidence: 99%

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Aberrant Expression of EZH2 in Pediatric Patients with Myelodysplastic Syndrome: A Potential Biomarker of Leukemic Evolution

Fernandez

Alvarenga

Kós

et al. 2019

BioMed Research International

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Pediatric myelodysplastic syndrome (MDS) is an uncommon disease and little is known about the molecular alterations of its development and evolution to acute myeloid leukemia (AML). The Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2 (PCR2). It is a histone methyltransferase, that targets lysine 27 of histone 3. This methylated H3–K27 is usually associated with the silencing of genes that are involved in fundamental cellular processes, such as cell proliferation and differentiation. There are only few studies showing the status of EZH2 expression in patients with MDS and they were performed in adult MDS patients. The aim of this study was to analyze the EZH2 expression in pediatric patients with MDS and its association with karyotypes and evolution to acute myeloid leukemia (AML). We conducted the first study of EZH2 expression in pediatric patients with MDS. Considering the EZH2 expression levels in 42 patients and 17 healthy pediatric donors, it was possible to define three groups of expression in patients: low, intermediate, and high. The intermediate level encompassed patients with normal karyotypes, low level included patients with monosomy 7 and del(7q) and high level included patients with trisomy 8 and del(11q) (p < 0.0001). Comparing the leukemic evolution, the low expression group presented disease evolution in 100% (8/8) of the cases, the intermediate expression group showed disease evolution in 4.34% (1/23) and in the high expression group, 63.63% (7/11) patients showed evolution from MDS to AML (p < 0.0001). It is important to note that low and high EZH2 expression are associated with leukemic evolution, however low expression showed a stronger association with evolution from MDS to AML than the high expression. Our results suggest a scale of measure for EZH2 expression in pediatric MDS, where aberrant EZH2 expression may be a potential biomarker of disease evolution.

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Epigenetic vulnerabilities of leukemia harboring inactivating EZH2 mutations

Alqazzaz,

Luciani,

et al. 2024

Experimental Hematology

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Association of EZH2 protein expression by immunohistochemistry in myelodysplasia related neoplasms with mutation status, cytogenetics and clinical outcomes

Cited by 6 publications

References 7 publications

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

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

Aberrant Expression of EZH2 in Pediatric Patients with Myelodysplastic Syndrome: A Potential Biomarker of Leukemic Evolution

Epigenetic vulnerabilities of leukemia harboring inactivating EZH2 mutations

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