Oncogenic deubiquitination controls tyrosine kinase signaling and therapy response in acute lymphoblastic leukemia.
Oncogenic deubiquitination controls tyrosine kinase signaling and therapy response in acute lymphoblastic leukemia.
复制标题
DOI：
10.1126/sciadv.abq8437
复制
发表时间：
2022-12-09
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
作者：
激酶信号通路的失调有利于肿瘤细胞的存活和治疗抵抗。在这里，我们揭示了在T细胞急性淋巴细胞白血病（T- all）中通过去泛素化对激酶信号和核受体活性的翻译后调控。我们观察到泛素特异性蛋白酶11 （USP11）在T-ALL中高表达并与不良预后相关。USP11消融术在体内抑制白血病进展，保留正常的造血功能。USP11与USP7形成复合物，使致癌淋巴细胞细胞特异性蛋白酪氨酸激酶（LCK）去泛素化并增强其活性。LCK活性受损导致糖皮质激素受体（GR）表达增加和糖皮质激素敏感性增加。基因敲除USP7可提高糖皮质激素在体内的抗白血病疗效。GR靶基因的转录激活由去泛素酶活性调控，并通过增强子-启动子相互作用强度的增加介导。我们的数据揭示了失调的去泛素化如何控制白血病的生存和耐药性，提示了以前未知的针对白血病的治疗组合。去泛素酶USP7和USP11增强LCK活性，阻碍T-ALL对糖皮质激素的反应。
Dysregulation of kinase signaling pathways favors tumor cell survival and therapy resistance in cancer. Here, we reveal a posttranslational regulation of kinase signaling and nuclear receptor activity via deubiquitination in T cell acute lymphoblastic leukemia (T-ALL). We observed that the ubiquitin-specific protease 11 (USP11) is highly expressed and associates with poor prognosis in T-ALL. USP11 ablation inhibits leukemia progression in vivo, sparing normal hematopoiesis. USP11 forms a complex with USP7 to deubiquitinate the oncogenic lymphocyte cell–specific protein-tyrosine kinase (LCK) and enhance its activity. Impairment of LCK activity leads to increased glucocorticoid receptor (GR) expression and glucocorticoids sensitivity. Genetic knockout of USP7 improved the antileukemic efficacy of glucocorticoids in vivo. The transcriptional activation of GR target genes is orchestrated by the deubiquitinase activity and mediated via an increase in enhancer-promoter interaction intensity. Our data unveil how dysregulated deubiquitination controls leukemia survival and drug resistance, suggesting previously unidentified therapeutic combinations toward targeting leukemia. The deubiquitinases USP7 and USP11 enhance LCK activity and hamper response to glucocorticoids in T-ALL.
登录
查看更多内容
影响因子：
20.3
作者：
Frismantas, Viktoras;Dobay, Maria Pamela;Bourquin, Jean-Pierre
通讯作者：
Bourquin, Jean-Pierre
USP7介导的乙酰化稳定DNMT1的分子机制
影响因子：
16.6
作者：
Cheng, Jingdong;Yang, Huirong;Fang, Jian;Ma, Lixiang;Gong, Rui;Wang, Ping;Li, Ze;Xu, Yanhui
通讯作者：
Xu, Yanhui
影响因子：
16.6
作者：
Huether, Robert;Dong, Li;Chen, Xiang;Wu, Gang;Parker, Matthew;Wei, Lei;Ma, Jing;Edmonson, Michael N.;Hedlund, Erin K.;Rusch, Michael C.;Shurtleff, Sheila A.;Mulder, Heather L.;Boggs, Kristy;Vadordaria, Bhavin;Cheng, Jinjun;Yergeau, Donald;Song, Guangchun;Becksfort, Jared;Lemmon, Gordon;Weber, Catherine;Cai, Zhongling;Dang, Jinjun;Walsh, Michael;Gedman, Amanda L.;Faber, Zachary;Easton, John;Gruber, Tanja;Kriwacki, Richard W.;Partridge, Janet F.;Ding, Li;Wilson, Richard K.;Mardis, Elaine R.;Mullighan, Charles G.;Gilbertson, Richard J.;Baker, Suzanne J.;Zambetti, Gerard;Ellison, David W.;Zhang, Jinghui;Downing, James R.
通讯作者：
Downing, James R.
影响因子：
10.1
作者：
Bandapalli, Obul R.;Zimmermann, Martin;Kulozik, Andreas E.
通讯作者：
Kulozik, Andreas E.
影响因子：
5
作者：
Brouwer, C;Vogels-Mentink, TM;De Abreu, RA
通讯作者：
De Abreu, RA