Disrupting pro-survival and inflammatory pathways with dimethyl fumarate sensitizes chronic lymphocytic leukemia to cell death.
Maria Elena MantioneMiriam MeloniIlenia SanaJessica BordiniMartina Del NeroMichela RibaPamela RanghettiEleonora PerottaPaolo GhiaLydia ScarfòMarta MuzioPublished in: Cell death & disease (2024)
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.
Keyphrases
- cell cycle arrest
- induced apoptosis
- oxidative stress
- cell death
- chronic lymphocytic leukemia
- signaling pathway
- pi k akt
- endoplasmic reticulum stress
- anti inflammatory
- acute myeloid leukemia
- rheumatoid arthritis
- peripheral blood
- climate change
- chronic kidney disease
- epithelial mesenchymal transition
- toll like receptor
- prognostic factors
- end stage renal disease
- gene expression
- dna methylation
- nuclear factor
- ejection fraction
- newly diagnosed
- artificial intelligence
- resting state