Cross NCP. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders

School of Medicine, University of Southampton, UK.
Nature Genetics (Impact Factor: 29.35). 08/2010; 42(8):722-6. DOI: 10.1038/ng.621
Source: PubMed


Abnormalities of chromosome 7q are common in myeloid malignancies, but no specific target genes have yet been identified. Here, we describe the finding of homozygous EZH2 mutations in 9 of 12 individuals with 7q acquired uniparental disomy. Screening of a total of 614 individuals with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals; the mutations were found most commonly in those with myelodysplastic/myeloproliferative neoplasms (27 out of 219 individuals, or 12%) and in those with myelofibrosis (4 out of 30 individuals, or 13%). EZH2 encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2), a highly conserved histone H3 lysine 27 (H3K27) methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions. EZH2 has oncogenic activity, and its overexpression has previously been causally linked to differentiation blocks in epithelial tumors. Notably, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies.

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    • "We purchased PRC2 complexes containing WT EZH2 (51004) or mutant EZH2 from BPS Bioscience [Morin et al., 2010]. Methyltransferase assays were done using a commonly used kit (17–330; EMD Millipore) [Ernst et al., 2010; Yap et al., 2011; Score et al., 2012] as per manufacturer's instructions. We incubated 250 ng of individual HMTase complexes separately with 0.67 μM 3 H-Sadenosyl-methionine ( 3 H-SAM) (Perkin Elmer, Waltham MA) and 2 μg core histones (or 1 μM peptide), in 50 mM Tris–HCl, pH 9.0, and 0.5 mM DTT for 30 min at 30°C in a 10 μl volume. "
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    ABSTRACT: Weaver syndrome (WS) is a rare congenital disorder characterized by generalized overgrowth, macrocephaly, specific facial features, accelerated bone age, intellectual disability, and susceptibility to cancers. De novo mutations in the enhancer of zeste homolog 2 (EZH2) have been shown to cause WS. EZH2 is a histone methyltransferase that acts as the catalytic agent of the polycomb-repressive complex 2 (PRC2) to maintain gene repression via methylation of lysine 27 on histone H3 (H3K27). Functional studies investigating histone methyltransferase activity of mutant EZH2 from various cancers have been reported, while WS-associated mutations remain poorly characterized. To investigate the role of EZH2 in WS, we performed functional studies using artificially-assembled PRC2 complexes containing mutagenized human EZH2 that reflected the codon changes predicted from patients with WS. We found that WS-associated amino acid alterations reduce the histone methyltransferase function of EZH2 in this in vitro assay. Our results support the hypothesis that WS is caused by constitutional mutations in EZH2 that alter the histone methyltransferase function of PRC2. However, histone methyltransferase activities of different EZH2 variants do not appear to correlate directly with the phenotypic variability between WS patients and individuals with a common c.553G>C (p.Asp185His) polymorphism in EZH2. This article is protected by copyright. All rights reserved.
    Full-text · Article · Dec 2015 · Human Mutation
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    • ". A heterozygous 5A3 deletion corresponding to human 7q22 perturbs steady-state hematopoiesis. (A) Top, candidate 7q myeloid tumor suppressor genes described previously (Asou et al., 2009; Ernst et al., 2010; Nikoloski et al., 2010; Zhou et al., 2011; McNerney et al., 2013; Chen et al., 2014; Hosono et al., 2014; Poetsch et al., 2014) appear above the diagram of chromosome 7q while commonly deleted segments (CDSs) within 7q22, 7q34, and 7q35-36 identified by different research groups (Kere et al., 1987a; Le Beau et al., 1996; Fischer et al., 1997; Liang et al., 1998; Tosi et al., 1999; Jerez et al., 2012; McNerney et al., 2013; Hosono et al., 2014) are Figure 1. continued on next page "
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    ABSTRACT: eLife digest Stem cells in the bone marrow are essential for creating new blood cells. Myelodysplastic syndrome (MDS) is a common type of blood cancer in the elderly that occurs when blood cells fail to develop normally. Depending on which types of blood cells are affected, individuals with MDS may bleed more easily, feel weak and tired, or be unable to effectively fight off infections. Animals and plants store their genetic information in the form of chromosomes. Humans have 23 pairs of chromosomes, with one copy inherited from the mother, and the other from the father. The bone marrow cells of many people with MDS delete a section from one of their copies of chromosome 7. As this section contains many different genes, it is difficult to fully understand which specific genes contribute to the development of MDS when one copy is lost. Wong et al. have now genetically engineered mice to lack a section of one of their copies of chromosome 7 that is often missing in patients with MDS. Bone marrow cells from these mice exhibit many of the same abnormalities found in human MDS. For example, most of the immature blood stem cells expand, but these stem cells do not correctly specialize into mature blood cells—in particular, not enough immune cells are produced. The developing blood cells also have problems expressing several genes, including one that helps to protect the cells from damaging molecules called reactive oxygen species. These problems worsen as the mice age. These mice provide the first evidence directly linking the missing section of chromosome 7 to abnormalities found in MDS patients. Future studies using the mice will advance our understanding of how the loss of this section of chromosome 7 interacts with other genes involved in MDS to alter the course of this disease and how it responds to treatment. DOI:
    Full-text · Article · Jul 2015 · eLife Sciences
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    • "In some types of cancer, EZH2 functions as a tumor suppressor. Inactivating mutations of EZH2 are found in patients with myeloid malignancies including myelodysplastic syndrome and myeloproliferative neoplasms, and such EZH2 mutations are associated with poor patient survival [108,109]. Mice with conditional deletions of EZH2 and TET2 in hematopoietic stem cells, the mutations of which frequently co-exist in myeloid malignancies, develop myelodysplastic syndrome and myeloproliferative neoplasms [110]. In addition to myeloid malignacies, 25% of T-cell leukemia cases have been shown to have loss-of-function mutations and deletions of the EZH2 and SUZ12 genes [111]. "
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    ABSTRACT: Polycomb repressive complex 2 (PRC2) is the epigenetic regulator that induces histone H3 lysine 27 methylation (H3K27me3) and silences specific gene transcription. Enhancer of zeste homolog 2 (EZH2) is an enzymatic subunit of PRC2, and evidence shows that EZH2 plays an essential role in cancer initiation, development, progression, metastasis, and drug resistance. EZH2 expression is indeed regulated by various oncogenic transcription factors, tumor suppressor miRNAs, and cancer-associated non-coding RNA. EZH2 activity is also controlled by post-translational modifications, which are deregulated in cancer. The canonical role of EZH2 is gene silencing through H3K27me3, but accumulating evidence shows that EZH2 methlyates substrates other than histone and has methylase-independent functions. These non-canonical functions of EZH2 are shown to play a role in cancer progression. In this review, we summarize current information on the regulation and roles of EZH2 in cancer. We also discuss various therapeutic approaches to targeting EZH2.
    Full-text · Article · Jul 2014 · Cancer Research and Treatment
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