Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders

Abstract

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.

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

“…This is consistent with the finding that EZH2 abnormalities are most common in CMML and MDS/ myelodysplastic-myeloproliferative neoplasms (MDS/MPN). 4 In addition, we observed no compound mutations of the EED and Letters to the Editor EZH2 genes (Figure 2a), strongly suggesting that these genes may independently affect PRC2 function.…”

Epigenetic cancer therapy: rationales, targets and drugs

“…Several studies have described overexpression of EZH2 in human cancers, including prostate and breast cancer, as well as in lymphoma (Varambally et al, 2002;Simon and Lange, 2008). Importantly, while cancer genome sequencing approaches detected inactivating EZH2 mutations in myeloid leukemias (Ernst et al, 2010;Nikoloski et al, 2010), they also uncovered specific heterozygous point mutations of EZH2 in lymphomas (Morin et al, 2010). These point mutations cause an enhanced capacity of EZH2 to di and trimethylate H3K27 (Sneeringer et al, 2010) and could thus drive the establishment of cancerspecific epigenetic programs.…”

Genetic changes of miR-182 G106A: rather a polymorphism than a somatic mutation

“…Based on chromosome banding analysis, two critical regions have been identified: one in band 7q22 and a second in bands 7q32-q35 1 . Molecular analyses of these two regions led to the identification of mutations in the EZH2 gene in MDS 2,3 .…”