EZH2 Y641 mutations in follicular lymphoma

Bödör, Csaba; O’Riain, Ciarán; Wrench, David; Matthews, Janet; Iyengar, Sunil; Tayyib, H; Calaminici, Maria; Clear, Andrew; Iqbal, Sameena; Quentmeier, Hilmar; Drexler, Hans G.; Montoto, Silvia; Lister, Andrew; Gribben, John G.; Matolcsy, András; Fitzgibbon, Jude

doi:10.1038/leu.2010.311

Cited by 124 publications

(75 citation statements)

References 14 publications

(25 reference statements)

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“…A variety of activating and inactivating mutations of EZH2 have been described in primary tumors derived from GCB DLBCLs, FLs, and myelodysplastic syndrome (1)(2)(3)(26)(27)(28). The end result of these mutations is increased or decreased methylation of H3K27 (16,17,26,28).…”

Section: Resultsmentioning

confidence: 99%

“…R ecent genome-wide sequencing studies have revealed several genes that are frequently altered in non-Hodgkin lymphomas, including EZH2, MLL2, MEF2B, CREBBP, and TP53 among others (1)(2)(3). Many of these genes mediate, either directly or indirectly, through the recruitment of cofactors, the array of posttranslational modifications observed on the amino-terminal tails of histones.…”

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confidence: 99%

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Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27)

McCabe

Graves

Ganji

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

427

425

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Trimethylation of histone H3 on lysine 27 (H3K27me3) is a repressive posttranslational modification mediated by the histone methyltransferase EZH2. EZH2 is a component of the polycomb repressive complex 2 and is overexpressed in many cancers. In B-cell lymphomas, its substrate preference is frequently altered through somatic mutation of the EZH2 Y641 residue. Herein, we identify mutation of EZH2 A677 to a glycine (A677G) among lymphoma cell lines and primary tumor specimens. Similar to Y641 mutant cell lines, an A677G mutant cell line revealed aberrantly elevated H3K27me3 and decreased monomethylated H3K27 (H3K27me1) and dimethylated H3K27 (H3K27me2). A677G EZH2 possessed catalytic activity with a substrate specificity that was distinct from those of both WT EZH2 and Y641 mutants. Whereas WT EZH2 displayed a preference for substrates with less methylation [unmethylated H3K27 (H3K27me0):me1:me2 k cat /K m ratio = 9:6:1] and Y641 mutants preferred substrates with greater methylation (H3K27me0:me1:me2 k cat /K m ratio = 1:2:13), the A677G EZH2 demonstrated nearly equal efficiency for all three substrates (H3K27me0:me1:me2 k cat /K m ratio = 1.1:0.6:1). When transiently expressed in cells, A677G EZH2, but not WT EZH2, increased global H3K27me3 and decreased H3K27me2. Structural modeling of WT and mutant EZH2 suggested that the A677G mutation acquires the ability to methylate H3K27me2 through enlargement of the lysine tunnel while preserving activity with H3K27me0/me1 substrates through retention of the Y641 residue that is crucial for orientation of these smaller substrates. This mutation highlights the interplay between Y641 and A677 residues in the substrate specificity of EZH2 and identifies another lymphoma patient population that harbors an activating mutation of EZH2.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27)

McCabe

Graves

Ganji

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

427

425

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“…Exons 16 and 18 of EZH2 were also analyzed by bidirectional Sanger sequencing, as described previously (supplemental Table 1 on the Blood Web site). 4,18 Subsequently, targeted resequencing of CREBBP, MLL2, TNFRSF14, and MEF2B was performed using the multiplex Access Array platform (Fluidigm) as per the manufacturer's recommendations in selected FL cases with EZH2 mutation (variant allele frequencies [VAF] range: 3.1% to 49.1%). Corrected VAF of EZH2 for the sequential FL-tFL cases were determined using tumor cell content estimates calculated by the ASCAT algorithm 19 using previously generated SNP6.0 array data.…”

Section: Mutation Analysismentioning

confidence: 99%

“…4,5 Mutations cluster to 3 codons, Y646, A682, and A692, are clonal in the majority of cases, and are stable during disease progression. The variable tumor content in FL biopsies supports the use of more sensitive and quantitative approaches during routine screening of FL to select patients with clonal EZH2 mutations, as these will be better suited for treatment with EZH2 inhibitors.…”

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confidence: 99%

“…(Blood. 2013; 122(18):3165-3168) Introduction Next-generation sequencing (NGS) studies have shown frequent mutations in epigenetic regulators in almost all cases of follicular lymphoma (FL).1,2 These include EZH2, the catalytic subunit of PRC2, which catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3), a repressive chromatin mark.3 Somatic gain-of-function mutations of EZH2 at codon Y646 (previously Y641) were identified in 7% to 22% of FLs and germinal center B-cell type diffuse large B-cell lymphomas leading to elevated H3K27 trimethylation [4][5][6][7][8] with mutations at codons A682 and A692 described in isolated cases of diffuse large B-cell lymphomas. 2,9-11 As highly selective EZH2 inhibitors have now been developed, [12][13][14] we set out to assess EZH2 mutation status, the effect of mutations on global gene expression, and the clonal representation of EZH2 mutations as the disease progresses.…”

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confidence: 99%

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EZH2 mutations are frequent and represent an early event in follicular lymphoma

Bödör

Großmann

Popov

et al. 2013

Blood

282

146

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Key Points• EZH2 mutations occur in more than 25% of follicular lymphoma patients.• Mutations predominantly represent an early/clonal event in the pathogenesis of the disease.Gain of function mutations in the H3K27 methyltransferase EZH2 represent a promising therapeutic target in germinal center lymphomas. In this study, we assessed the frequency and distribution of EZH2 mutations in a large cohort of patients with follicular lymphoma (FL) (n 5 366) and performed a longitudinal analysis of mutation during the disease progression from FL to transformed FL (tFL) (n 5 33). Mutations were detected at 3 recurrent mutation hot spots (Y646, A682, and A692) in 27% of FL cases with variant allele frequencies (VAF) ranging from 2% to 61%. By comparing VAF of EZH2 with other mutation targets (CREBBP, MLL2, TNFRSF14, and MEF2B), we were able to distinguish patients harboring clonal EZH2 mutation from rarer cases with subclonal mutations. Overall, the high incidence of EZH2 mutations in FL and their stability during disease progression makes FL an appropriate disease to evaluate EZH2 targeted therapy. (Blood. 2013; 122(18):3165-3168) Introduction Next-generation sequencing (NGS) studies have shown frequent mutations in epigenetic regulators in almost all cases of follicular lymphoma (FL).1,2 These include EZH2, the catalytic subunit of PRC2, which catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3), a repressive chromatin mark.3 Somatic gain-of-function mutations of EZH2 at codon Y646 (previously Y641) were identified in 7% to 22% of FLs and germinal center B-cell type diffuse large B-cell lymphomas leading to elevated H3K27 trimethylation [4][5][6][7][8] with mutations at codons A682 and A692 described in isolated cases of diffuse large B-cell lymphomas. 2,9-11 As highly selective EZH2 inhibitors have now been developed, [12][13][14] we set out to assess EZH2 mutation status, the effect of mutations on global gene expression, and the clonal representation of EZH2 mutations as the disease progresses. Study design Patient samplesGenomic DNA from 181 diagnostic FL patients with accompanying clinical and gene expression data 15 were obtained through the Lymphoma/Leukemia Molecular Profiling Project consortium. DNA from 185 additional FL patients (56 obtained at diagnosis and 129 at relapse) and 33 paired FL and transformed FL (tFL) samples were sourced from the tissue archive at the Barts Cancer The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734.The publisher or recipient acknowledges right of the US government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.BLOOD, 31 OCTOBER 2013 x VOLUME 122, NUMBER 18 3165For personal use only. on May 9, 2018. by guest www.bloodjournal.org From Institute. The study was approved by the London Research Ethical Committee (05/Q0605/140) and was conducted in accordance with the...

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