2024-03-28T10:58:22Z
https://nagoya.repo.nii.ac.jp/oai
oai:nagoya.repo.nii.ac.jp:00025716
2023-01-16T04:16:24Z
499:500:501
Altered EZH2 splicing and expression is associated with impaired histone H3 lysine 27 tri-Methylation in myelodysplastic syndrome
Shirahata-Adachi, Mizuho
Iriyama, Chisako
Tomita, Akihiro
Suzuki, Yasuhiro
Shimada, Kazuyuki
Kiyoi, Hitoshi
open access
© 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
EZH2
H3K27 methyltransferase
Myelodysplastic syndromes
Background: 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. Material and methods: 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. Results: 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. Conclusion: 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.
ファイル公開日: 2018/12/01
Elsevier
2017-12
eng
journal article
AM
http://hdl.handle.net/2237/00027924
https://nagoya.repo.nii.ac.jp/records/25716
https://doi.org/10.1016/j.leukres.2017.10.015
01452126
Leukemia Research
63
90
97
https://nagoya.repo.nii.ac.jp/record/25716/files/Shirahata_Adachi_Mizuho.pdf
application/pdf
5.7 MB
2018-12-01