Down-regulation of EZH2 expression in myelodysplastic syndromes.

EZH2 genetic mutations are common in myelodysplastic syndrome (MDS), which implies that this gene has a pathophysiological role in the disease. To further characterize molecular alterations of EZH2, and their potential prognostic impact in MDS, we assessed EZH2 RNA expression in primary bone marrow CD34+ cells from 78 patients. We found that 47% of patients have reduced EZH2 expression compared to normal controls. Further analyses revealed that EZH2 is significantly underexpressed in patients bearing chromosome 7 or 7q deletions (7-alt) when compared to controls, diploid patients, and patients with other cytogenetic alterations (p<0.05). In survival analysis, we found a non-significant trend toward overall survival (OS) being better among patients with EZH2 underexpression (median OS 55 vs. 36 months; p=0.71). Importantly, this trend became significant when the analysis was restricted to the subset of cases without alterations in chromosome 7 (62 vs. 36 months; p=0.033). Furthermore, our previous work has identified a spectrum of innate immune genes in MDS CD34+ cells that are deregulated via abnormal promoter histone methylation. Because EZH2 is a key regulator of histone methylation, we assessed the relationship between deregulation of these genes and EZH2 underexpression. We observed that the mRNA levels of 11 immune genes were higher in the EZH2 underexpression group and that immune gene expression was significantly higher in patients with concomitant EZH2 underexpression and KDM6B (also known as JMJD3, an H3K27 demethylase) overexpression. Taken together, these data indicate that EZH2 underexpression may have unique impact on the molecular pathogenesis and prognosis in MDS and be an important marker for patients without chromosome 7 alteration.

Cabrero M ，Wei Y ，Yang H ，Ganan-Gomez I ，Bohannan Z ，Colla S ，Marchesini M ，Bravo GM ，Takahashi K ，Bueso-Ramos C ，Garcia-Manero G ... -  《-》

The KDM2B- let-7b -EZH2 axis in myelodysplastic syndromes as a target for combined epigenetic therapy.

Karoopongse E ，Yeung C ，Byon J ，Ramakrishnan A ，Holman ZJ ，Jiang PY ，Yu Q ，Deeg HJ ，Marcondes AM ... -  《PLoS One》

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

Xu F ，Li X ，Wu L ，Zhang Q ，Yang R ，Yang Y ，Zhang Z ，He Q ，Chang C ... -  《-》

Altered EZH2 splicing and expression is associated with impaired histone H3 lysine 27 tri-Methylation in myelodysplastic syndrome.

EZH2 (enhancer of zeste homolog 2) is a histone H3K27 methyltransferase involved in the pathogenesis of various hematological malignancies. In myelodysplastic syndromes (MDS), loss of function of EZH2 is known to contribute to pathogenesis, however the pattern of EZH2 mRNA and protein expression in MDS has not been extensively characterized. A total of 26 patients diagnosed with MDS were analyzed in this study. The relationship between EZH2 expression in patient bone marrow samples, evaluated by RT-PCR and immunoblotting, and patient characteristics were analyzed. The function of truncated EZH2 proteins was examined in vitro. EZH2 expression levels and transcript sizes varied considerably between patients, but there was no relationship with the percentage blast component of patient samples. Cloning and sequencing of amplified RT-PCR fragments demonstrated that patients expressed multiple EZH2 transcripts containing insertions or deletions, with or without frameshift, mainly induced by altered splicing. All identified frameshift mutations were found to be 5' to the functional SET domain, and resulted in truncated protein translation. Altered patterns of EZH2 expression was observed in patients with or without alterations in genes involved with RNA splicing, SRSF2, U2AF1 and SF3B1. Functional analysis in vitro revealed that C-terminally truncated EZH2, lacking the SET domain, may impair the methyltransferase function of wild-type EZH2 in a dominant negative fashion. Our findings suggest that the loss of function of EZH2 induced by aberrant splicing, and/or EZH2 mutations resulting in the production of C-terminally truncated proteins, may be involved in MDS pathogenesis.

Shirahata-Adachi M ，Iriyama C ，Tomita A ，Suzuki Y ，Shimada K ，Kiyoi H ... -  《-》

Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells.

Wei Y ，Chen R ，Dimicoli S ，Bueso-Ramos C ，Neuberg D ，Pierce S ，Wang H ，Yang H ，Jia Y ，Zheng H ，Fang Z ，Nguyen M ，Ganan-Gomez I ，Ebert B ，Levine R ，Kantarjian H ，Garcia-Manero G ... -  《-》