Dimethyl itaconate selectively targets inflammatory and metabolic pathways in chronic lymphocytic leukemia

• DOI: 10.1002/eji.202350418
• Publication Date: 2023-08-10T20:09:10Z
• Authors: Ilenia Sana; Maria Elena Mantione; Miriam Meloni; Michela Riba; Pamela Ranghetti; Lydia Scarfò; Paolo Ghia; Marta Muzio
• Keywords: Proinflammatory cytokine

Chronic lymphocytic leukemia (CLL) co-evolves with its own microenvironment where inflammatory stimuli including toll-like receptors (TLR) signaling can protect CLL cells from spontaneous and drug-induced apoptosis by upregulating IκBζ, an atypical co-transcription factor. To dissect IκBζ-centered pathways, we performed a gene expression profile of primary leukemic expressing either high or low levels IκBζ after stimulation, highlighting that is not only but it may control metabolic rewiring malignant thus pointing to novel potential opportunity for therapy. We exploited the capacity dimethyl itaconate (DI), anti-inflammatory electrophilic synthetic derivative metabolite Itaconate, target IκBζ. cells, murine splenocytes, leukocytes healthy donors were treated in vitro DI abolished activation reduced cell viability only, even presence robust TLR prestimulation. RNA sequencing highlighted addition expected stress signature observed treatment, pathways emerged downregulation distinct MHC class II complex genes. In conclusion, abrogated proinflammatory effects stimulation also targeted specific vulnerability cells.