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Published in: Journal of Cancer Research and Clinical Oncology 7/2016

01-07-2016 | Original Article – Clinical Oncology

EZH2 mutations and promoter hypermethylation in childhood acute lymphoblastic leukemia

Authors: Vivien Schäfer, Jana Ernst, Jenny Rinke, Nils Winkelmann, James F. Beck, Andreas Hochhaus, Bernd Gruhn, Thomas Ernst

Published in: Journal of Cancer Research and Clinical Oncology | Issue 7/2016

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Abstract

Purpose

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and young adults. The polycomb repressive complex 2 (PRC2) has been identified as one of the most frequently mutated epigenetic protein complexes in hematologic cancers. PRC2 acts as an epigenetic repressor through histone H3 lysine 27 trimethylation (H3K27me3), catalyzed by the histone methyltransferase enhancer of zeste homolog 2 protein (EZH2).

Methods

To study the prevalence and clinical impact of PRC2 aberrations in an unselected childhood ALL cohort (n = 152), we performed PRC2 mutational screenings by Sanger sequencing and promoter methylation analyses by quantitative pyrosequencing for the three PRC2 core component genes EZH2, suppressor of zeste 12 (SUZ12), and embryonic ectoderm development (EED). Targeted deep next-generation sequencing of 30 frequently mutated genes in leukemia was performed to search for cooperating mutations in patients harboring PRC2 aberrations. Finally, the functional consequence of EZH2 promoter hypermethylation on H3K27me3 was studied by Western blot analyses of primary cells.

Results

Loss-of-function EZH2 mutations were detected in 2/152 (1.3 %) patients with common-ALL and early T-cell precursor (ETP)-ALL, respectively. In one patient, targeted deep sequencing identified cooperating mutations in ASXL1 and TET2. EZH2 promoter hypermethylation was found in one patient with ETP-ALL which led to reduced H3K27me3. In comparison with healthy children, the EZH2 promoter was significantly higher methylated in T-ALL patients. No mutations or promoter methylation changes were identified for SUZ12 or EED genes, respectively.

Conclusions

Although PRC2 aberrations seem to be rare in childhood ALL, our findings indicate that EZH2 aberrations might contribute to the disease in specific cases. Hereby, EZH2 promoter hypermethylation might have functionally similar consequences as loss-of-function mutations.
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Metadata
Title
EZH2 mutations and promoter hypermethylation in childhood acute lymphoblastic leukemia
Authors
Vivien Schäfer
Jana Ernst
Jenny Rinke
Nils Winkelmann
James F. Beck
Andreas Hochhaus
Bernd Gruhn
Thomas Ernst
Publication date
01-07-2016
Publisher
Springer Berlin Heidelberg
Published in
Journal of Cancer Research and Clinical Oncology / Issue 7/2016
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-016-2174-8

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Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine