当前位置: X-MOL 学术Br. J. Haematol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
USP7 inhibition inhibits proliferation and induces megakaryocytic differentiation in MDS cells by upregulating gelsolin.
British Journal of Haematology ( IF 5.1 ) Pub Date : 2020-03-04 , DOI: 10.1111/bjh.16549
Jinghui Deng 1, 2 , Long Liang 1, 2 , Hui Yi 2 , Tao Su 1 , Zhou Yang 3 , Ling Nie 1 , Jing Liu 2
Affiliation  

Myelodysplastic syndrome (MDS), a largely incurable hematological malignancy, is driven by complex genetic and epigenetic alterations from an aberrant clone of hematopoietic stem/progenitor cells (HSPCs). Ubiquitin‐specific protease 7 (USP7) has been demonstrated to have an important oncogenic role in the development of several cancer types, but its role in MDS is unknown. Here, we demonstrate that USP7 expression is elevated in MDS cell lines and patient samples. The USP7‐selective small‐molecule inhibitors P5091 and P22077 inhibited cell proliferation and induced megakaryocytic differentiation in both cell lines and primary cells. Furthermore, pharmacological inhibition of USP7 markedly suppressed the growth of MDS cell lines in xenograft mouse models. To explore the mechanisms underlying the observed phenotypic changes, we employed RNA‐seq to compare the differences in genes after USP7 inhibitor treatment and found that gelsolin (GSN) expression was increased significantly after USP7 inhibitor treatment. Furthermore, knockdown of GSN attenuated the proliferation inhibition, apoptosis induction and megakaryocyte differentiation induced by USP7 inhibitors in MDS cells. Collectively, our findings identify previously unknown roles of USP7 and suggest that the USP7/GSN axis may be a potential therapeutic target in MDS.

中文翻译:

通过上调凝溶胶蛋白,USP7抑制作用抑制MDS细胞的增殖并诱导巨核细胞分化。

骨髓增生异常综合症(MDS)是一种很大程度上无法治愈的血液系统恶性肿瘤,由造血干/祖细胞(HSPCs)异常克隆产生的复杂遗传和表观遗传学变化驱动。泛素特异性蛋白酶7(USP7)已被证明在几种癌症类型的发展中具有重要的致癌作用,但其在MDS中的作用尚不清楚。在这里,我们证明了MDS细胞系和患者样品中USP7的表达升高。USP7选择性小分子抑制剂P5091和P22077在细胞系和原代细胞中均抑制细胞增殖并诱导巨核细胞分化。此外,USP7的药理抑制作用显着抑制了异种移植小鼠模型中MDS细胞系的生长。为了探索观察到的表型变化的潜在机制,我们使用RNA-seq比较USP7抑制剂处理后基因的差异,发现USP7抑制剂处理后凝溶胶蛋白(GSN)表达显着增加。此外,GSN的敲低减弱了USP7抑制剂在MDS细胞中诱导的增殖抑制,凋亡诱导和巨核细胞分化。总的来说,我们的发现确定了USP7以前未知的作用,并暗示USP7 / GSN轴可能是MDS的潜在治疗靶标。
更新日期:2020-03-04
down
wechat
bug