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.

核因子红细胞 2 相关因子 2（Nrf2，也称为 NFE2L2）在癌症化学抗性中起重要作用。然而，关于 Nrf2 在肿瘤突变负荷中的作用以及 Nrf2 在调节急性髓系白血病 (AML) 中 DNA 错配修复 (MMR) 基因中的作用知之甚少。在这里，我们表明 Nrf2 表达与 AML 中的肿瘤突变负荷相关。Nrf2 过度表达的患者基因突变和耐药性的频率更高。Nrf2 过表达保护 AML 细胞免受体外阿糖胞苷诱导的细胞凋亡，并增加了与体内基因突变相关的耐药风险。此外，Nrf2 过表达抑制了 MutS 同源 2 (MSH2) 蛋白表达，从而导致 DNA MMR 缺陷。从机制上讲，Nrf2 对 MSH2 的抑制是以与 ROS 无关的方式进行的。进一步的研究表明，Nrf2 过表达细胞中 JNK/c-Jun 信号的激活增加抑制了 MSH2 蛋白的表达。我们的研究结果提供证据表明，高 Nrf2 表达可在 AML 中诱导基因不稳定性依赖性耐药性。本研究证明了Nrf2高表达导致AML基因突变频率增加的原因，为临床实践提供了新的策略。