Abstract
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.
Highlights
Acute myeloid leukemia (AML) is a malignant tumor of myeloid progenitor cells characterized by immature myeloid cell proliferation and bone marrow failure
AML patient specimens were divided into two groups either expressing high or low levels of Nrf[2] based on Quantitative real-time PCR (qRT-PCR), using the median Nrf[2] expression levels as cut-off values
Patients in the Nrf2-High group had more blast cells and less remission after standard chemotherapy, which had a higher risk of relapse or drug resistance (Fig. 1b)
Summary
Acute myeloid leukemia (AML) is a malignant tumor of myeloid progenitor cells characterized by immature myeloid cell proliferation and bone marrow failure. Most patients die of their disease due to either refractory (initial resistance to chemotherapy) or relapsed AML3. The resistance of leukemia cells to chemotherapy drugs becomes the main obstacle in the treatment of AML. Many hypotheses have been proposed to explain therapeutic resistance in AML, including the persistence of leukemic stem cells[4], increased antioxidant defense systems[5], altered expression of drug influx and efflux transporters[6], evasion of cell death[7], and epigenetic mechanisms including DNA methylation and histone modification[8,9]. Tumor cells are insensitive to chemotherapeutic drugs, due to the presence of complex abnormal karyotypes of chromosomes and gene mutations[11]. Exploring the molecular mechanism of gene instability-dependent drug resistance is a significant strategy to overcome the chemoresistance and relapse
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