Stabilization of SAMHD1 by NONO is crucial for Ara-C resistance in AML.
Stabilization of SAMHD1 by NONO is crucial for Ara-C resistance in AML.
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DOI：
10.1038/s41419-022-05023-0
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发表时间：
2022-07-08
影响因子：
9
通讯作者：
Lv, Xiao-Bin
中科院分区：
文献类型：
--
作者：
Zhang, Feifei;Sun, Jun;Tang, Xiaofeng;Liang, Yiping;Jiao, Quanhui;Yu, Bo;Dai, Zhengzai;Yuan, Xuhui;Li, Jiayu;Yan, Jinhua;Zhang, Zhiping;Fan, Song;Wang, Min;Hu, Haiyan;Zhang, Changhua;Lv, Xiao-Bin
阿糖胞苷（Ara-C）是治疗急性髓性白血病（AML）的一线药物。然而，耐药性最终产生，降低了Ara-C在AML患者中的疗效。SAMHD1是一种脱氧核苷三磷酸（dNTP）三磷酸水解酶，据报道，SAMHD1在Ara-C耐药的AML患者中表达升高，并在介导Ara-C耐药的AML中发挥关键作用。然而，SAMHD1在耐药AML中上调的机制尚不清楚。在这项研究中，NONO通过抑制dcaf1介导的SAMHD1泛素化/降解与SAMHD1相互作用并稳定SAMHD1。NONO的过表达增加了SAMHD1的表达，降低了AML细胞对Ara-C的敏感性，而NONO的下调则具有相反的作用。此外，dna损伤剂DDP和阿霉素（ADM）降低NONO/SAMHD1的表达，使AML细胞对Ara-C敏感。更重要的是，NONO在Ara-C耐药AML细胞中上调，导致SAMHD1在耐药AML细胞中的表达增加，DDP和ADM处理使耐药AML细胞对Ara-C重新敏感。本研究揭示了SAMHD1在ara - c耐药AML细胞中上调的机制，为ara - c耐药AML提供了新的治疗策略。
Cytarabine (Ara-C) is the first-line drug for the treatment of acute myelogenous leukemia (AML). However, resistance eventually develops, decreasing the efficacy of Ara-C in AML patients. The expression of SAMHD1, a deoxynucleoside triphosphate (dNTP) triphosphohydrolase, has been reported to be elevated in Ara-C-resistant AML patients and to play a crucial role in mediating Ara-C resistance in AML. However, the mechanism by which SAMHD1 is upregulated in resistant AML remains unknown. In this study, NONO interacted with and stabilized SAMHD1 by inhibiting DCAF1-mediated ubiquitination/degradation of SAMHD1. Overexpression of NONO increased SAMHD1 expression and reduced the sensitivity of AML cells to Ara-C, and downregulation of NONO had the opposite effects. In addition, the DNA-damaging agents DDP and adriamycin (ADM) reduced NONO/SAMHD1 expression and sensitized AML cells to Ara-C. More importantly, NONO was upregulated in Ara-C-resistant AML cells, resulting in increased SAMHD1 expression in resistant AML cells, and DDP and ADM treatment resensitized resistant AML cells to Ara-C. This study revealed the mechanism by which SAMHD1 is upregulated in Ara-C-resistant AML cells and provided novel therapeutic strategies for Ara-C-resistant AML.
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影响因子：
11.1
作者：
Ling Q;Li F;Zhang X;Mao S;Lin X;Pan J;Ye W;Wei W;Qian Y;Hu C;Huang X;Wang J;Wang H;Huang J;Wang Y;Jin J
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影响因子：
2.6
作者：
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影响因子：
4.4
作者：
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通讯作者：
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影响因子：
8
作者：
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通讯作者：
Pentimalli, F.
DOI：
10.1080/15384101.2017.1314407
发表时间：
2017-06-03
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Herold N;Rudd SG;Sanjiv K;Kutzner J;Bladh J;Paulin CBJ;Helleday T;Henter JI;Schaller T
通讯作者：
Schaller T