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Nuclear factor erythroid 2-related factors 1 and 2 are able to define the worst prognosis group among high-risk diffuse large B cell lymphomas treated with R-CHOEP
Open accessAbstract
Aims: Oxidative stress markers and antioxidant enzymes have previously been shown to have prognostic value and associate with adverse outcome in patients with diffuse large B cell lymphoma (DLBCL). Nuclear factor erythroid 2-related factor 1 (Nrf1) and factor 2 (Nrf2) are among the principal inducers of antioxidant enzyme production. Kelch ECH associating protein 1 (Keap1) is a negative regulator of Nrf2, and BTB (BR-C, ttk and bab) domain and CNC homolog 1 (Bach1) represses the function of both factors. Their significance in DLBCL prognosis is unknown. Methods: Diagnostic biopsy samples of 76 patients with high-risk DLBCL were retrospectively stained with immunohistochemistry for Nrf1, Nrf2, Keap1 and Bach1, and correlated with clinical data and outcome. Results: Nuclear Nrf2 and nuclear Bach1 expression were associated with adverse clinical features (anaemia, advanced stage, high IPI, high risk of neutropaenic infections), whereas cytoplasmic Nrf1 and Nrf2 were associated with favourable clinical presentation (normal haemoglobin level, no B symptoms, limited stage). None of the evaluated factors could predict survival alone. However, when two of the following parameters were combined: high nuclear score of Nrf2, low nuclear score of Nrf1, high cytoplasmic score of Nrf1 and low cytoplasmic score of Keap1 were associated with significantly worse overall survival. Conclusions: Nrf1 and Nrf2 are relevant in disease presentation and overall survival in high-risk DLBCL. Low nuclear expression of Nrf1, high cytoplasmic expression of Nrf1, high nuclear expression of Nrf2 and low cytoplasmic expression of Keap1 are associated with adverse outcome in this patient group.
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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 [38]
The Discussion (page unavailable) links high Nrf2 levels to chemoresistance and reduced radiotherapy sensitivity, and reports Nrf-related chemoresistance in multiple myeloma. It does not attribute those effects to NRF2-activating mutations or establish radiation resistance specifically in lymphoma. The citing sentence assigns the leukemia and solid-tumor portions to other references. (LLM, conf=0.85)
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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
“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].”
Background
Metadata
- Authors
- Kari, E., Teppo, H.-R., Haapasaari, K.-M., Kuusisto, M. E. L., Lemma, A., Karihtala, P., Pirinen, R., Soini, Y., Jantunen, E., Turpeenniemi-Hujanen, T., & Kuittinen, O.
- Affiliations
- Oulu University Hospital (FI)
- North Karelia Central Hospital (FI)
- University of Eastern Finland (FI)
- Kuopio University Hospital (FI)
- Corresponding author
- Kari, Esa
- ORCID
- Venue
- Journal of Clinical Pathology
- Publisher
- BMJ
- Published
- 2019-02-12
- Volume
- 72
- Issue
- 4
- Pages
- 316-321
- ISSN
- 0021-9746 (ISSN-L)
- 1472-4146
- PMC
- PMC6580789
- OpenAlex
- W2913511582
- Cited by
- 16
- References
- 1
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 4 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 2
- FWCI
- 1.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Journal of Clinical Pathology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Suomen Lääketieteen Säätiö
- Finska Läkaresällskapet
- Suomalainen Lääkäriseura Duodecim
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Clinical Neurology › CNS Lymphoma Diagnosis and Treatment
- Keywords
- diffuse large B-cell lymphoma, NRF1, Nrf2, Keap1, BACH1, prognostic factors, overall survival, oxidative stress, antioxidant enzymes, high-risk DLBCL, subcellular protein localization
- MeSH terms
- Rituximab, Kelch-Like ECH-Associated Protein 1, Antineoplastic Agents, Immunological, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Cell Nucleus, Cyclophosphamide, Cytoplasm, Doxorubicin, Etoposide, Female, Humans, Immunohistochemistry, Male, Middle Aged, Neoplasm Staging, Predictive Value of Tests, Prednisolone, Retrospective Studies, Risk Factors, Biomarkers, Tumor, Vincristine, Lymphoma, Large B-Cell, Diffuse, Treatment Outcome, Risk Assessment, Basic-Leucine Zipper Transcription Factors, NF-E2-Related Factor 1, NF-E2-Related Factor 2, Young Adult
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