Overexpression of the EZH2, RING1 and BMI1 genes is common in myelodysplastic syndromes: relation to adverse epigenetic alteration and poor prognostic scoring

Abstract

Epigenetics refers to the study of clonally inherited changes in gene expression without accompanying genetic changes. Previous research on the epigenetics of myelodysplastic syndromes (MDS) mainly focused on the inactivation of tumor suppressor genes as a result of DNA methylation. However, the basic molecular pathogenesis of epigenetics in MDS remains poorly understood. Recent studies have revealed that DNA methylation and histone modification may be controlled by Polycomb-group (PcG) proteins, which may give new clues toward understanding the epigenetic mechanism of MDS. In this study, we explored for the first time the expression of PcG genes, including EZH2, EED, SUZ12, RING1, and BMI1, in various MDS subsets and acute myeloid leukemia (AML), as well as the relationship between the expression of PcG genes and epigenetic alteration and prognosis-risk scoring. Patients with MDS/AML showed overexpression of EZH2, RING1, and BMI1 genes compared to their expression levels in patients with non-clonal cytopenia diseases. The MDS patients with DNA methylation had higher EZH2 expression than those without DNA methylation. The patients who received decitabine treatment presented significantly reduced expression of EZH2 and RING1 besides decreased p15(INK4B) methylation after decitabine treatment. Moreover, overexpression of EZH2, RING1, and BMI1 was always linked to poor prognostic scoring. In conclusion, overexpression of the EZH2, RING1, and BMI1 genes is common in MDS and indicate poor prognosis. The products of these genes might participate in epigenetic regulation of MDS. These studies may also contribute to our understanding of the effective mechanism of decitabine.

Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease

“…Moreover, mutation of Ezh2 Y641 has been described in lymphomas 7 and results in Ezh2 gain-of-function 8,9 . Oncogenic activity of Ezh2 has also been described in myelodysplastic syndromes 10 and in acute myeloid leukaemia 11 , where it has been identified as a potential drug target 12 . However, acquired Ezh2 mutations in myeloid neoplasms have also been found, indicating that Ezh2 may act as a tumour suppressor 13,14 .…”

Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A

“…35 The foregoing mutations in CMML will help to reconcile the existence of a presumptive reduction of H3K27me3 levels because of EZH2 heterozygosity or homozygosity and loss-of-function of the histone H3K27 demethylase UTX. In addition, overexpression of EZH2 has been reported in patients with AML and with MDS, 43 most probably resulting in silencing of genes involved in differentiation. Loss of UTX activity would be enzymatically equivalent to a gain of function for EZH2 or simply overexpression of this enzyme.…”

The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and Is Disrupted in Cancer

“…Although we cannot exclude that the BAP1/ASXL1/2 target other known substrates such HCF-1 and OGT (19,23), our study and others provide strong support for the role of this DUB in the regulation of H2Aub levels and tumor suppression. Indeed (i) BAP1 was revealed as a major DUB for H2A in mammalian cells; (ii) several cancer mutations of BAP1 and ASXL2 target the UCH/CC1/CTD/ASXM platform, which is critical for ubiquitin binding and H2A deubiquitination, (iii) BAP1 null cancer cells display high H2Aub levels that could be reduced following reintroduction of BAP1, but not ASXL1/2 interaction-deficient mutants, (iv) both PcG proteins Ring1B and BMI1, two critical components of the PRC1 complex that catalyze H2A ubiquitination, regulate cell proliferation and are overexpressed in cancer (63)(64)(65). Thus, our study provides further insights into the potential involvement of H2Aub in tumorigenesis.…”