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DNMT3A R882H mutation drives daunorubicin resistance in acute myeloid leukemia via regulating NRF2/NQO1 pathway
Cell Communication and Signaling ( IF 8.4 ) Pub Date : 2022-10-27 , DOI: 10.1186/s12964-022-00978-1
Xuan Chu 1 , Liang Zhong 2 , Wenran Dan 1 , Xiao Wang 1 , Zhonghui Zhang 1 , Zhenyan Liu 1 , Yang Lu 1 , Xin Shao 1 , Ziwei Zhou 1 , Shuyu Chen 1 , Beizhong Liu 1, 2
Affiliation  

DNA methyltransferase 3A (DNMT3A) often mutate on arginine 882 (DNMT3AR882) in acute myeloid leukemia (AML). AML patients with DNMT3A R882 mutation are usually resistant to daunorubicin treatment; however, the associated mechanism is still unclear. Therefore, it is urgent to investigate daunorubicin resistance in AML patients with DNMT3A R882 mutant. AML cell lines with DNMT3A-wild type (DNMT3A-WT), and DNMT3A-Arg882His (DNMT3A-R882H) mutation were constructed to investigate the role of DNMT3A R882H mutation on cell proliferation, apoptosis and cells’ sensitivity to Danunorubin. Bioinformatics was used to analyze the role of nuclear factor-E2-related factor (NRF2) in AML patients with DNMT3A R882 mutation. The regulatory mechanism of DNMT3A R882H mutation on NRF2 was studied by Bisulfite Sequencing and CO-IP. NRF2 inhibitor Brusatol (Bru) was used to explore the role of NRF2 in AML cells carried DNMT3A R882H mutation. AML cells with a DNMT3A R882H mutation showed high proliferative and anti-apoptotic activities. In addition, mutant cells were less sensitive to daunorubicin and had a higher NRF2 expression compared with those in WT cells. Furthermore, the NRF2/NQO1 pathway was activated in mutant cells in response to daunorubicin treatment. DNMT3A R882H mutation regulated the expression of NRF2 via influencing protein stability rather than decreasing methylation of NRF2 promoter. Also, NRF2/NQO1 pathway inhibition improved mutant cells’ sensitivity to daunorubicin significantly. Our findings identified NRF2 as an important player in the regulation of cell apoptosis through which helps mediate chemoresistance to daunorubicin in AML cells with DNMT3A R882H mutation. Targeting NRF2 might be a novel therapeutic approach to treat AML patients with a DNMT3A R882H mutation.

中文翻译:

DNMT3A R882H 突变通过调节 NRF2/NQO1 通路驱动急性髓性白血病柔红霉素耐药

在急性髓性白血病 (AML) 中,DNA 甲基转移酶 3A (DNMT3A) 经常在精氨酸 882 (DNMT3AR882) 上发生突变。具有 DNMT3A R882 突变的 AML 患者通常对柔红霉素治疗有耐药性;然而,相关机制仍不清楚。因此,迫切需要研究具有DNMT3A R882突变体的AML患者对柔红霉素的耐药性。构建具有 DNMT3A-野生型 (DNMT3A-WT) 和 DNMT3A-Arg882His (DNMT3A-R882H) 突变的 AML 细胞系,以研究 DNMT3A R882H 突变对细胞增殖、凋亡和细胞对达努红红素敏感性的作用。采用生物信息学分析核因子-E2相关因子(NRF2)在DNMT3A R882突变的AML患者中的作用。通过亚硫酸氢盐测序和 CO-IP 研究了 DNMT3A R882H 突变对 NRF2 的调控机制。NRF2 抑制剂 Brusatol (Bru) 用于探索 NRF2 在携带 DNMT3A R882H 突变的 AML 细胞中的作用。具有 DNMT3A R882H 突变的 AML 细胞显示出高增殖和抗凋亡活性。此外,与野生型细胞相比,突变细胞对柔红霉素的敏感性较低,并且具有更高的 NRF2 表达。此外,NRF2/NQO1 通路在突变细胞中响应柔红霉素处理被激活。DNMT3A R882H 突变通过影响蛋白质稳定性而不是降低 NRF2 启动子的甲基化来调节 NRF2 的表达。此外,抑制 NRF2/NQO1 通路可显着提高突变细胞对柔红霉素的敏感性。我们的研究结果确定 NRF2 是调节细胞凋亡的重要参与者,通过它有助于介导具有 DNMT3A R882H 突变的 AML 细胞对柔红霉素的化学耐药性。靶向 NRF2 可能是治疗具有 DNMT3A R882H 突变的 AML 患者的一种新型治疗方法。
更新日期:2022-10-27
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