The high Nrf2 expression in human acute myeloid leukemia is driven by NF-κB and underlies its chemo-resistance
Open accessAbstract
NF-E2–related factor 2 (Nrf2) transcription factor regulates a range of cytoprotective transcriptional responses, preventing further cellular injury by removing biochemical damage and renewing tissue. Here we show that acute myeloid leukemia (AML) cells possess greater constitutive nuclear levels of Nrf2 than normal control CD34+ cells because of an imbalance between mRNA expression levels of Nrf2 and its inhibitor Keap1 but not through their somatic mutation. Elevated Nrf2 was reduced by NF-κB inhibitors. Using promoter assays, ChIP and siRNA knockdown, we demonstrated NF-κB subunits p50 and p65 induce transcription of Nrf2 in AML cells at a specific promoter κB-site and that long-term lentiviral miRNA-knockdown of Nrf2 significantly reduced clonogenicity of AML patient cells and improved their chemotherapeutic responsiveness. Normal physiologic Nrf2 protects cells from damage, but here we have exposed aberrant continuous nuclear activation of Nrf2 in AML that allows cell survival, even against cytotoxic chemotherapeutics. We show for the first time that Nrf2, an important regulator of several biologic processes involved in the progression of cancer, has abnormal NF-κB–driven constitutive expression in AML. Such a mechanism allows for a greater cytoprotective response in human AML cells and encourages their evasion of chemotherapy-induced cytotoxicity, which is necessary for improved clinical outcomes.
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NRF2-activating mutations have been associated with chemo- and radiation resistance in lymphoma, leukemia, and solid tumors.
“NRF2-activating mutations are rare in untreated lymphomas; however, they have been associated with chemo- and radiation resistance in lymphoma [37,38], leukemia [39], and in solid tumors [40].”
From NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy (2021) · cites this paper as [39]
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NRF2, a Transcription Factor for Stress Response and Beyond
He, F., Ru, X., & Wen, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21134777 · Cited by 1,820 · see citing works
Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways
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The role of transcription factor Nrf2 in skin cells metabolism
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Cancer-Derived Mutations in KEAP1 Impair NRF2 Degradation but not Ubiquitination
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p53 as a hub in cellular redox regulation and therapeutic target in cancer
Eriksson, S. E., Ceder, S., Bykov, V. J. N., & Wiman, K. G. (2019) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjz005 · Cited by 123 · see citing works
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Self-citationNrf2 Transcription Factor Can Directly Regulate mTOR
Bendavit, G., Aboulkassim, T., Hilmi, K., Shah, S., & Batist, G. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.760249 · Cited by 95 · see citing works
Yu, X., Wang, Y., Tan, J., Li, Y., Yang, P., Liu, X., Lai, J., Zhang, Y., Cai, L., Gu, Y., et al. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-01800-2 · Cited by 48 · see citing works
NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy
Sanghvi, V. R., Mohan, P., Singh, K., Cao, L., Berishaj, M., Wolfe, A. L., Schatz, J. H., Lailler, N., de Stanchina, E., Viale, A., et al. (2021) · Cancers · doi:10.3390/cancers13040639 · Cited by 27 · see citing works
“NRF2‐activating mutations are rare in untreated lymphomas; however, they have been associated with chemo‐ and radiation resistance in lymphoma [37,38], leukemia [39], and in solid tumors [40].”
BackgroundCuadrado, A., Cazalla, E., Bach, A., Bathish, B., Naidu, S. D., DeNicola, G. M., Dinkova-Kostova, A. T., Fernández-Ginés, R., Grochot-Przeczek, A., Hayes, J. D., et al. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103569 · Cited by 28 · see citing works
- Authors
- Rushworth, S. A., Zaitseva, L., Murray, M. Y., Shah, N. M., Bowles, K. M., & MacEwan, D. J.
- Affiliations
- University of East Anglia (GB)
- Norfolk and Norwich University Hospital (GB)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2012-12-20
- Volume
- 120
- Issue
- 26
- Pages
- 5188-5198
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2055196208
- Cited by
- 290
- References
- 4
- Citations by year
- 2026: 7 · 2025: 20 · 2024: 25 · 2023: 24 · 2022: 25 · 2021: 35 · 2020: 33 · 2019: 23 · 2018: 18 · 2017: 20 · 2016: 15 · 2015: 15 · 2014: 15 · 2013: 15
- FWCI
- 5.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- Nrf2, acute myeloid leukemia, NF-κB, chemoresistance, Keap1, p50/p65, transcriptional regulation, cytoprotection, chemotherapy-induced cytotoxicity, clonogenicity, microRNA knockdown
- MeSH terms
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Tumor Cells, Cultured, Leukemia, Myeloid, Acute, Up-Regulation, Gene Expression Regulation, Leukemic, NF-kappa B, HL-60 Cells, Drug Resistance, Neoplasm, U937 Cells, NF-E2-Related Factor 2
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