Disrupting pro-survival and inflammatory pathways with dimethyl fumarate sensitizes chronic lymphocytic leukemia to cell death

Abstract

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.

Nrf2 regulates the activation-driven expansion of CD4+T-cells by differentially modulating glucose and glutamine metabolism

“…Accordingly, the levels of Gln, glutamate, and a-KG were high in these cells. With a myriad of Nrf2-activating drugs being tested in pre-clinical and clinical trials for various diseases and inflammatory conditions 60,[69][70][71] , it is highly significant to understand how high Nrf2 affects T-cell activation and their immunometabolism. In summary, we uncover an important role of Nrf2 in regulating the nutrient dependency and metabolism of activated CD4 + T-cells to govern their activation and expansion thus paving the way for the utilization of metabolism as a tool for improving the existing Nrf2-based therapeutics including T-cell immunotherapies.…”