Jason Gotlib, MD, MS
Dr. Gotlib indicated no relevant conflicts of interest.
Ernst T, Chase AJ, Score J, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet. 2010;42:722-726.
Nikoloski G, Langemeijer SM, Kuiper RP, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet. 2010;42:665-667.
Knowledge of specific chromosomal abnormalities in myeloid disorders has allowed partitioning of patients into subgroups that carry prognostic import. While the discovery of genes involved in recurrent reciprocal translocations has been relatively uncomplicated, identification of disease-relevant genes in regions of large chromosomal alterations (e.g., deletions of chromosome 5/5q or 7/7q) has been challenging. In this regard, the use of high-resolution SNP arrays to identify regions of acquired uniparental disomy (UPD) and subsequent somatic alterations in the genes for JAK2 (9p24), CBL (11q), and TET2 (4q24) illustrates the utility of this approach.
Shared regions of chromosome 7 deletions are relatively common in MDS and AML and are associated with poor outcomes. Two studies, from the teams led by Nicholas Cross from the United Kingdom and Joop Jansen from the Netherlands, used SNP arrays to uncover UPD in chromosome region 7q36.1 and identified acquired somatic mutations in the gene encoding the histone methyltransferase EZH2 in patients with MDS, MPN, and overlap MDS/MPNs. As part of the polycomb repressive complex 2 (PRC2), EZH2 catalyzes the addition of a trimethyl mark on histone H3 lysine 27 (H3K27), resulting in epigenetic modification via gene silencing.
In a survey of myeloid disorders, Cross’ group found EZH2 mutations in 42 of 614 patients (6.8%), including a relatively higher frequency (27 of 219, 12%) in individuals with MDS/MPN. In Jansen and colleagues’ study of MDS patients, 8 of 126 subjects (6%) exhibited point mutations, and the EZH2 locus was deleted by micro- or large-scale chromosome 7 deletions in an additional 22 individuals. Notably, no EZH2 mutations were found in 54 AML patients with complete or partial monosomy for chromosome 7. In both analyses, genetic alterations included missense, donor-splice site, and frameshift mutations, with a small proportion of patients demonstrating biallelic mutations. Missense mutations were commonly found in the CXC-SET catalytic domains, which are required for histone methyltransferase activity. In vitro histone methylation assays and cell lines with mutant EZH2 demonstrated loss of histone H3K27 trimethylation, consistent with abrogation of methyltransferase activity. EZH2 mutations were associated with a worse prognosis in MDS/MPN patients, with less clear evidence for adverse outcomes in subjects with MDS.
The spectrum of mutations in EZH2 in patients with myeloid disorders is distinct from the singular and recurrent heterozygous mutations of residue Tyr641 in follicular and diffuse large B-cell lymphomas, which also exhibit reduced ability to trimethylate H3K27.1 In these diseases, loss of EZH2 function suggests it has a role as a putative tumor suppressor. Conversely, overexpression of EZH2 with progression of malignancies such as breast and prostate carcinomas suggests it could function as an oncogene.2,3 However, its direct role in subverting cell growth versus it being an epiphenomenal marker of cancerous potential requires further investigation. In addition to EZH2, a recent report of mutations in the H3K27 demethylase gene UTX in a variety of cancers4 and a role for Tet2 in DNA methylation highlight the interplay between specific components of the epigenetic machinery and neoplastic transformation. The value of determining EZH2 mutation status in predicting response to hypomethylating therapy will be of particular interest.
- Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42:181-185.
- Kleer CG, Cao Q, Varambally S, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA. 2003;100:11606-11611.
- Varambally S, Dhanasekaran SM, Zhou M, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002;419:624-629.
- van Haaften G, Dalgliesh GL, Davies H, et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet. 2009;41:521-523.
back to top