Disrupting pro-survival and inflammatory pathways with dimethyl fumarate sensitizes chronic lymphocytic leukemia to cell death
Open accessAbstract
Microenvironmental signals strongly influence chronic lymphocytic leukemia (CLL) cells through the activation of distinct membrane receptors, such as B-cell receptors, and inflammatory receptors, such as Toll-like receptors (TLRs). Inflammatory pathways downstream of these receptors lead to NF-κB activation, thus protecting leukemic cells from apoptosis. Dimethyl fumarate (DMF) is an anti-inflammatory and immunoregulatory drug used to treat patients with multiple sclerosis and psoriasis in which it blocks aberrant NF-κB pathways and impacts the NRF2 antioxidant circuit. Our in vitro analysis demonstrated that increasing concentrations of DMF reduce ATP levels and lead to the apoptosis of CLL cells, including cell lines, splenocytes from Eµ-TCL1-transgenic mice, and primary leukemic cells isolated from the peripheral blood of patients. DMF showed a synergistic effect in association with BTK inhibitors in CLL cells. DMF reduced glutathione levels and activated the NRF2 pathway; gene expression analysis suggested that DMF downregulated pathways related to NFKB and inflammation. In primary leukemic cells, DMF disrupted the TLR signaling pathways induced by CpG by reducing the mRNA expression of NFKBIZ, IL6, IL10 and TNFα. Our data suggest that DMF targets a vulnerability of CLL cells linked to their inflammatory pathways, without impacting healthy donor peripheral blood mononuclear cells.
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Differentiated cell types such as kidney cells, microglia or neurons express high levels of SALL1, 2 and 3.
“differentiated cell types such as kidney cells 57 , microglia 58 or neurons 59 express high levels of SALL1, 2 and 3”
From Tetramerisation governs SALL transcription factor function in development and disease (2025) · cites this paper as [59]
The Introduction and Materials and methods discuss chronic lymphocytic leukemia and genes such as NRF2, not SALL1, SALL2 or SALL3. Searches for SALL expression in kidney cells, microglia and neurons found no passage in our copy addressing the claim. A reference to microglia and neurons concerns dimethyl fumarate, not SALL expression. (LLM, conf=0.76)
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Vlachonikola, E., Sofou, E., Chatzidimitriou, A., Stamatopoulos, K., & Agathangelidis, A. (2021) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2021.03.003 · Cited by 7 · see citing works
Flagged first, then by citations
2 of the 68 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- [8]Byrd JC Harrington B O’Brien S Jones JA Schuh A Devereux S Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia N Engl J Med 2016 374 323 32 26641137 PMC4862586
- [15]Mansouri L Sutton LA Ljungström V Bondza S Arngården L Bhoi S Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia J Exp Med 2015 212 833 43 25987724 PMC4451125
Cited by
Sorted by citations
Targeting oxidative stress-mediated regulated cell death as a vulnerability in cancer
Chen, D., Guo, Z., Yao, L., Sun, Y., Dian, Y., Zhao, D., Ke, Y., Zeng, F., Zhang, C., Deng, G., et al. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103686 · Cited by 88 · see citing works
“This property has shown promise in treating hematological malignancies, including diffuse large B-cell lymphoma and chronic lymphocytic leukemia [459,460].”
Reactive oxygen species: Janus-faced molecules in the era of modern cancer therapy
O’Reilly, A., Zhao, W., Wickström, S. L., Arnér, E. S. J., & Kiessling, R. W. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-009409 · Cited by 42 · see citing works
Fumarate integrates metabolism and immunity in diseases
Cheng, J., Xiao, Y., & Jiang, P. (2025) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2025.03.008 · Cited by 23 · see citing works
Xi, C.-X., Pang, J.-F., Xue, W., Cui, Y., Jiang, N., Zhi, W.-B., Shi, H.-D., Horuzsko, A., Pace, B. S., & Zhu, X.-G. (2025) · Communications Biology · doi:10.1038/s42003-024-07424-7 · Cited by 21 · see citing works
“Interestingly,DMFisalsoshowntoregulateferroptosisinatime-dependent manner,inducingferroptosisinashortperiodbutrepressingferroptosisina longperiod 58 .”
Nrf2 Activation in Inflammatory Diseases: A Review of Natural and Synthetic Modulators
Costa, V. B., de Matos, I. A. F., Nogueira, I. R. G., de Godoi, M. A., Leite, F. R. M., & Guimarães, M. R. (2026) · Oxidative Medicine and Cellular Longevity · doi:10.1155/omcl/4538420 · Cited by 15 · see citing works
Gan, X., Li, J.-W., Jiang, Y., Wang, X., Zeng, Y.-Q., Chen, X., Huang, H., Min, J., Li, G., Nie, M., et al. (2025) · Phytomedicine · doi:10.1016/j.phymed.2025.156697 · Cited by 14 · see citing works
Tripathi, A., Dasgupta, D., Dahabieh, M., Griffard-Smith, R., Pant, A., Bugbee, A., Yellapu, N., Burt, E., Choi, B. H. Y., Ellis, A. E., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116177 · Cited by 13 · see citing works
“With a myriad of Nrf2-activating drugs being tested in pre-clinical and clinical trials for various diseases and inflammatory conditions, 67,76–78 it is necessary to understand how high Nrf2 affects T cell activation and immunometabolism.”
Maihemuti, N., Shi, Y.-L., Zhang, K., Jiang, X., Chu, J., Xu, Y., Xu, Z.-Y., & Wang, K. (2025) · MedComm · doi:10.1002/mco2.70308 · Cited by 12 · see citing works
“In leukemia patients, signals within the tumor microenvironment activate TLR/NF-κ B signaling, thereby preventing apoptosis [142].”
Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure
Roe, A., Dowling, C., D'Arcy, C., Rodrigues, D. A., Wang, Y., Hiller, M., Keogh, C., Hollinshead, K. E. R., Garrè, M., Cavanagh, B., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-61897-6 · Cited by 8 · see citing works
“There are also clinicaltrials assessing DMF in relapsed chronic lymphocytic leukaemia 44 and cutaneous T cell lymphoma 45 .”
The emerging fungal pathogen <i>Candida auris</i> induces IFNγ to colonize mammalian hair follicles
Merrill, E. D., Prudent, V., Moghadam, P., Rodriguez, A., Hurabielle, C., Wells, E. K. C., Basso, P., Scharschmidt, T. C., Rosenblum, M. D., Molofsky, A. B., et al. (2025) · doi:10.1101/2025.01.15.632653 · Cited by 4 · see citing works
Wu, A., Jin, Y., Chen, Y., Pan, K., Jiang, Q., Tian, L., Lai, F., Liu, N., Wang, X., Pan, J., et al. (2025) · Phytomedicine · doi:10.1016/j.phymed.2025.157487 · Cited by 4
Tripathi, A., Dasgupta, D., Pant, A., Bugbee, A., Yellapu, N., Choi, B. H. Y., Giri, S., & Pyaram, K. (2024) · bioRxiv · doi:10.1101/2024.04.18.590146 · Cited by 3 · see citing works
“With a myriad of Nrf2-activating drugs being tested in pre-clinical and clinical trials for various diseases and inflammatory conditions 60,69–71 , it is highly significant to understand how high Nrf2 affects T-cell activation and their immunometabolism.”
BackgroundZhang, R., Kan, Y., Liu, H., Pan, P., Hu, X., Xu, Y., Wang, J.-H., & Wang, J. (2026) · Cellular Immunology · doi:10.1016/j.cellimm.2026.105083 · Cited by 2
Targeting Epstein-Barr virus (EBV) for treatment of multiple sclerosis
Soldan, S. S., Messick, T. E., & Lieberman, P. M. (2026) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2026.107066 · Cited by 1 · see citing works
Tetramerisation governs SALL transcription factor function in development and disease
Giuliani, S., Chhatbar, K., Wear, M., Guy, J., Mathieson, T., Burdett, H., George, L., Alston, G., Spanos, C., McHugh, T., et al. (2025) · bioRxiv · doi:10.1101/2025.10.27.684836
IκBζ target genes in chronic lymphocytic leukemia
Sana, I., Meloni, M., Genova, F., Mantione, M. E., Tascini, A., Zapparoli, E., Faccin, G. C., Paschaloudi, D., Nero, M. D., Lenzi, C., et al. (2026) · iScience · doi:10.1016/j.isci.2026.117828
“21,22 However, the genome-wide direct target genes regulated by I κ B ζ in B cell neoplasia remain largely undefined.”
Self-citationShirooie, S., Heidarizade, N., Noori, T., Sureda, A., Iranpanah, A., & Alibeygi, S. (2026) · Iranian journal of pharmaceutical research · doi:10.5812/ijpr-170319
“When NF-kB is overactivated and Nrf2 signaling is impaired, a damaging cycle of neuroinflammation and oxidative stress can occur (28, 32, 33).”
- Authors
- Mantione, M. E., Meloni, M., Sana, I., Bordini, J., Del Nero, M., Riba, M., Ranghetti, P., Perotta, E., Ghia, P., Scarfò, L., & Muzio, M.
- Affiliations
- IRCCS Ospedale San Raffaele (IT)
- Vita-Salute San Raffaele University (IT)
- Corresponding author
- Muzio, Marta
- ORCID
- Venue
- Cell Death & Disease
- Published
- 2024-03-18
- Volume
- 15
- Issue
- 3
- Pages
- 224-224
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC10944843
- OpenAlex
- W4392925327
- Cited by
- 57
- References
- 68
- Citations by year
- 2026: 13 · 2025: 37 · 2024: 7
- FWCI
- 16.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Associazione Italiana per la Ricerca sul Cancro (IG-2019-ID. 23088, IG-27566)
- Topics
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- chronic lymphocytic leukemia, dimethyl fumarate, apoptosis, NF-κB signaling, Toll-like receptor signaling, Nrf2 signaling, BTK inhibitors, glutathione depletion, CpG, tumor microenvironment, drug repurposing, interleukin-6, IL-10, TNF-α, NFKBIZ
- MeSH terms
- Dimethyl Fumarate, Animals, Humans, Leukocytes, Mononuclear, Mice, Transgenic, Leukemia, Lymphocytic, Chronic, B-Cell, NF-kappa B, Apoptosis, NF-E2-Related Factor 2, Mice
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