NRF2 activation induced by PML‐RARα promotes microRNA 125b‐1 expression and confers resistance to chemotherapy in acute promyelocytic leukemia

Abstract

Dear Editor,Chromosomal translocation is a hallmark of acute myeloid leukemia (AML), often leading to gene rearrangements and expression of a fusion oncoprotein. 1 In this work, we described the fusion oncoprotein promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) as a new mechanism for nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) activation during leukemogenesis and suggest that PML-RARα-induced NRF2/miR-125b-1 is uniformly important in reactive oxygen species (ROS) detoxification and the antileukemia response.We have previously shown that PML-RARα resulting from t(15;17) translocation, leads to aberrantly high expression of microRNA 125b-1 (miR-125b-1) in acute promyelocytic leukemia (APL, M3 subtype of AML). 2 In this study, we wanted to understand the mechanism by which PML-RARα regulates miR-125b-1. Although the central role of fusion oncoprotein in the pathogenesis of AML has been recognized for a long time, and previous reports have suggested that activation of NRF2 mediates upregulation of miR-125b-1 in AML, 3,4 there is little known about the mechanism of NRF2 activation and how PML-RARα regulates miR-125b-1. Similar to previous studies, 3 NRF2 was expressed at high levels in primary APL samples compared to healthy individuals (HIs), as well as in non-APL AML (Figures S1A-S1C). Notably, we observed that NRF2 was predominantly located in the cytoplasm in HIs and those AML in CR (Complete Remission); however, it was mainly in the nucleus in primary APL and non-APL AML (Figures 1A and S1D). Importantly, PML-RARα could significantly enhance the protein level of NRF2 (Figure 1B) without effect on its mRNA (Figure S1E). Analysis of NRF2 in the cytosolic and nuclear fractions indicated that PML-RARα induced constitutive nuclear levels of NRF2 (Figures 1C, 1D, and S1F).This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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“…Jurkat T cells were transfected using the Neon ® Transfection System (Invitrogen) with 100 pmol of oligonucleotides in 10 μl reactions [ 43 – 45 ]. Briefly, 2 × 10 5 cells were suspended in 100 pmol of oligonucleotides in 10 μl reactions, and each 12-well plate was transfected four times.…”

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“…qRT-PCR was performed with a qRT-PCR kit (TIANGEN, Beijing, China), and β-actin was used as an internal control. 24,27 Relative expression levels were calculated as a 2 -ΔΔCt method. The primers for qRT-PCR are shown in Table S2.…”

“…(version:2.0.4). 24 High-quality reads were mapped to the human reference genome (GRCh38), and the expression level of each gene was calculated as fragments per kilobase of exon model per million mapped reads.…”

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“…Similarly, Bae et al [ 26 ] reported that sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage. Although numerous studies have determined that Nrf2 can be regulated by many proteins in numerous biological processes, such as PML-RAR α , the question of whether it is regulated by STAT6 has not been studied thus far [ 27 , 28 ].…”