Novel homo- and hemizygous mutations in EZH2 in myeloid malignancies

EED mutants impair polycomb repressive complex 2 in myelodysplastic syndrome and related neoplasms

“…We suggest that, in addition to inactivating mutations of catalytic EZH2, [3][4][5] non-catalytic EED mutations exclusively perturb PRC2-mediated epigenetic regulation and substantially contribute to the pathogenesis of MDS and related diseases (Figure 2b). Recently, Score et al 14 reported a set of defective gene mutations of PRC2 constituents, including an EED point mutation, Gly255Asp, in 148 MDS/MPN cases.…”

EZH2 Y641 mutations in follicular lymphoma

“…Although we observed a 100-fold difference in both miR-101 and miR-26a expression levels across samples, these did not correlate with EZH2 levels in either t(14;18)-positive cell lines or FL primary material (data not shown). Whereas in myeloid malignancies EZH2 mutation leads to a clear loss of function, [4][5][6] Morin et al previously showed that Y641 mutations result in a reduction of the H3K27 trimethylation capacity in vitro. 1 In contrast, our results showed H3K27me3 expression in all FL samples irrespective of their mutation status (Figure 2b), suggesting that these Y641 mutations are unlikely to behave in a dominant-negative fashion in FL.…”

“…3 The spectrum of cancers with EZH2 mutation is also increasing, with mutations in myeloid disorders leading to reduced or complete loss of H3K27me3 expression consistent with a tumour suppressor role for EZH2. [4][5][6] Deregulation of the EZH2-H3K27me3 pathway may also occur by other mechanisms, with over-expression of EZH2 associated with poor outcome in a range of solid tumours. [7][8][9] In this study, we set out to determine the prevalence and the prognostic value of EZH2 Y641 variants in a large cohort of patients with FL, and the relationship between mutation and EZH2 and H3K27me3 expression.…”

A somatic EZH2 mutation in childhood acute myeloid leukemia

“…In adult AML, an EZH2 mutation has been identified in a single case of a 65-yearold man with acute myelomonocytic leukemia (FAB type M4) in a total of 143 de novo AML cases screened so far. 9,11 Functionally distinct EZH2 missense mutations affecting a single amino acid (Y641) have been reported in patients with follicular and diffused large B-cell lymphomas of germinal-center origin resulting in a gain of function. 12 Accepted article preview online 23 January 2012; advance online publication, 10 February 2012 EZH2 encodes the catalytic subunit of the polycomb repressive complex 2, a highly conserved histone H3 lysine 27 (H3K27) methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions.…”

“…7 --13 Large follow-up studies demonstrated that cMBL carries a risk of progression into CLL requiring treatment of about 1 --4% per year, the occurrence of SLL being the most frequent disease evolution, detected in 15% of MBL cases. 7,10,11 The clinical course of cMBL is far from being clearly defined and discussion exists on whether the current guidelines could be improved to better discriminate the individuals affected by MBL from those suffering from CLL. It is matter of debate which B-cell cut-off value could better distinguish patients bound to progress and which factors (and in particular if any CLL prognostic features) might predict the risk of developing a symptomatic disease.…”