Nrf2 overexpression increases risk of high tumor mutation burden in acute myeloid leukemia by inhibiting MSH2.
Nrf2 overexpression increases risk of high tumor mutation burden in acute myeloid leukemia by inhibiting MSH2.
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Nrf2 过表达通过抑制 MSH2 增加急性髓系白血病高肿瘤突变负担的风险
DOI：
10.1038/s41419-020-03331-x
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发表时间：
2021-01-05
影响因子：
9
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Liu P;Ma D;Wang P;Pan C;Fang Q;Wang J
核因子红细胞2相关因子2（Nrf 2，也称为NFE 2L 2）在癌症化疗耐药性中起重要作用。然而，Nrf 2在肿瘤突变负荷中的作用以及Nrf 2在调节急性髓系白血病（AML）DNA错配修复（MMR）基因中的作用知之甚少。在这里，我们发现Nrf 2表达与AML中的肿瘤突变负荷相关。Nrf 2过表达的患者有较高的基因突变频率和耐药性。Nrf 2过表达在体外可保护AML细胞免受阿糖胞苷诱导的凋亡，并在体内增加与基因突变相关的耐药风险。此外，Nrf 2过表达抑制MutS Homolog 2（MSH 2）蛋白表达，导致DNA MMR缺陷。Nrf 2对MSH 2的抑制机制不依赖于ROS。进一步的研究表明，在Nrf 2过表达细胞中JNK/c-Jun信号转导的激活增加抑制了MSH 2蛋白的表达。我们的研究结果提供了证据表明，高Nrf 2表达可以诱导AML的基因不稳定性依赖性耐药。本研究揭示了AML中Nrf 2高表达导致基因突变频率增加的原因，为临床实践提供了新的策略。
Nuclear factor erythroid 2-related factor 2 (Nrf2, also called NFE2L2) plays an important role in cancer chemoresistance. However, little is known about the role of Nrf2 in tumor mutation burden and the effect of Nrf2 in modulating DNA mismatch repair (MMR) gene in acute myeloid leukemia (AML). Here we show that Nrf2 expression is associated with tumor mutation burden in AML. Patients with Nrf2 overexpression had a higher frequency of gene mutation and drug resistance. Nrf2 overexpression protected the AML cells from apoptosis induced by cytarabine in vitro and increased the risk of drug resistance associated with a gene mutation in vivo. Furthermore, Nrf2 overexpression inhibited MutS Homolog 2 (MSH2) protein expression, which caused DNA MMR deficiency. Mechanistically, the inhibition of MSH2 by Nrf2 was in a ROS-independent manner. Further studies showed that an increased activation of JNK/c-Jun signaling in Nrf2 overexpression cells inhibited the expression of the MSH2 protein. Our findings provide evidence that high Nrf2 expression can induce gene instability-dependent drug resistance in AML. This study demonstrates the reason why the high Nrf2 expression leads to the increase of gene mutation frequency in AML, and provides a new strategy for clinical practice.
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影响因子：
82.9
作者：
通讯作者：
--
影响因子：
2.4
作者：
Gunes, S.;Agarwal, A.;Sabanegh, E.
通讯作者：
Sabanegh, E.
影响因子：
4.8
作者：
Humbert, O;Hermine, T;Lautier, D
通讯作者：
Lautier, D
DOI：
10.1002/cjp2.120
发表时间：
2019-04
期刊：
The journal of pathology. Clinical research
影响因子：
--
作者：
McCarthy AJ;Capo-Chichi JM;Spence T;Grenier S;Stockley T;Kamel-Reid S;Serra S;Sabatini P;Chetty R
通讯作者：
Chetty R
影响因子：
3.7
作者：
Karathedath S;Rajamani BM;Musheer Aalam SM;Abraham A;Varatharajan S;Krishnamurthy P;Mathews V;Velayudhan SR;Balasubramanian P
通讯作者：
Balasubramanian P