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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    • "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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    • "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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    • "Mutations in ASXL1 have been identified in MDS, AML, chronic myeloid leukemia, chronic myelomonocytic leukemia (CMML), and juvenile myelomonocytic leukemia [50-54], and act as a tumor suppressor in myeloid malignancies [50]. Mutations in ASXL1, TET2, and EZH2 have been found in 41% of MDS cases in a Chinese population [44], similar to the data reported in patients of European decent with MDS [21,23,24,55,56]. "
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    ABSTRACT: Advances in genome-wide molecular cytogenetics allow identification of novel submicroscopic DNA copy number alterations (aCNAs) and copy-neutral loss of heterozygosity (cnLOH) resulting in homozygosity for known gene mutations in myeloid neoplasms. We describe the use of an oligo-SNP array for genomic profiling of aCNA and cnLOH, together with sequence analysis of recurrently mutated genes, in a patient with myelodysplastic syndrome (MDS) presenting with normal karyotype and FISH results. Oligo-SNP array analysis revealed a hemizygous deletion of 896 kb at chromosome 5q31.2, representing the smallest 5q deletion reported to date. The deletion involved multiple genes, including two tumor suppressor candidate genes (CTNNA1 and HSPA9) that are associated with MDS/AML. The SNP-array study also detected 3 segments of somatic cnLOH: one involved the entire long arm of chromosome 4; the second involved the distal half of the long arm of chromosome 7, and the third encompassed the entire chromosome 22 (UPD 22). Sequence analysis revealed mutations in TET2 (4q), EZH2 (7q), ASXL1 (20q11.21), and RUNX1 (21q22.3). Coincidently, TET2 and EZH2 were located at segments of cnLOH resulting in their homozygosity. Loss of heterozygosity affecting these two chromosomes and mutations in TET2 and EZH2 are indicative of a myelodysplastic syndrome with a poor prognosis. Deletion of the tumor suppressor genes CTNNA1 and HSPA9 is also likely to contribute to a poor prognosis. Furthermore, the original cnLOHs in multiple chromosomes and additional cnLOH 14q in the follow-up study suggest genetic evolution of the disease and poor prognosis. This study attests to the fact that some patients with a myelodysplastic syndrome who exhibit a normal karyotype may have underlying genetic abnormalities detectable by chromosomal microarray and/or targeted mutation analyses.
    Molecular Cytogenetics 05/2014; 7(1):35. DOI:10.1186/1755-8166-7-35 · 2.14 Impact Factor
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