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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    • ". 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: Chromosome 7 deletions are highly prevalent in myelodysplastic syndrome (MDS), and likely contribute to aberrant growth through haploinsufficiency. We generated mice with a heterozygous germline deletion of a 2 Mb interval of chromosome band 5A3 syntenic to a commonly deleted segment of human 7q22, and show that mutant hematopoietic cells exhibit cardinal features of MDS. Specifically, the long-term hematopoietic stem cell (HSC) compartment is expanded in 5A3(+/del) mice, and the distribution of myeloid progenitors (MP) is altered. 5A3(+/del) HSCs are defective for lymphoid repopulating potential and show a myeloid lineage output bias. These cell autonomous abnormalities are exacerbated by physiologic aging and upon serial transplantation. The 5A3 deletion partially rescues defective repopulation in Gata2 mutant mice. 5A3(+/del) hematopoietic cells exhibit decreased expression of oxidative phosphorylation genes, increased levels of reactive oxygen species, and perturbed oxygen consumption. These studies provide the first functional data linking 7q22 deletions to MDS pathogenesis.
    eLife Sciences 07/2015; 4. DOI:10.7554/eLife.07839 · 9.32 Impact Factor
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    • "The detection of recurrent somatic LOH has contributed to the identification of novel mutations associated with myeloid oncogenesis, such as JAK2 in MPD (23) and TET2 (24) and FZH2 (25) in AML. In addition, recurrent somatic LOH indicates a mechanism by which leukemic cells can increase the dose of the mutated gene (15). "
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    ABSTRACT: The combined array comparative genomic hybridization plus single-nucleotide polymorphism microarray (CGH+SNP microarray) platform can simultaneously detect copy number alterations (CNA) and copy-neutral loss of heterozygosity (LOH). Eighteen children with acute myeloid leukemia (AML) (n=15) or myelodysplastic syndrome (MDS) (n=3) were studied using CGH+SNP microarray to evaluate the clinical significance of submicroscopic chromosomal aberrations. CGH+SNP microarray revealed CNAs at 14 regions in 9 patients, while metaphase cytogenetic (MC) analysis detected CNAs in 11 regions in 8 patients. Using CGH+SNP microarray, LOHs>10 Mb involving terminal regions or the whole chromosome were detected in 3 of 18 patients (17%). CGH+SNP microarray revealed cryptic LOHs with or without CNAs in 3 of 5 patients with normal karyotypes. CGH+SNP microarray detected additional cryptic CNAs (n=2) and LOHs (n=5) in 6 of 13 patients with abnormal MC. In total, 9 patients demonstrated additional aberrations, including CNAs (n=3) and/or LOHs (n=8). Three of 15 patients with AML and terminal LOH>10 Mb demonstrated a significantly inferior relapse-free survival rate (P=0.041). This study demonstrates that CGH+SNP microarray can simultaneously detect previously cryptic CNAs and LOH, which may demonstrate prognostic implications. Graphical Abstract
    Journal of Korean Medical Science 07/2014; 29(7):926-33. DOI:10.3346/jkms.2014.29.7.926 · 1.27 Impact Factor
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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.
    Cancer Research and Treatment 07/2014; 46(3):209-222. DOI:10.4143/crt.2014.46.3.209 · 3.32 Impact Factor
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