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

Abstract

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 signaling pathways, we performed a gene expression profile of primary leukemic cells expressing either high or low levels of IκBζ after stimulation, highlighting that IκBζ is not only an inflammatory gene but it may control metabolic rewiring of malignant cells thus pointing to a novel potential opportunity for therapy. We exploited the capacity of the Dimethyl Itaconate (DI), an anti‐inflammatory electrophilic synthetic derivative of the metabolite Itaconate, to target IκBζ. CLL cells, murine leukemic splenocytes, and leukocytes from healthy donors were treated in vitro with DI that abolished metabolic activation and reduced cell viability of leukemic cells only, even in the presence of robust TLR pre‐stimulation. RNA sequencing highlighted that in addition to the expected electrophilic stress signature observed after DI treatment, novel pathways emerged including the downregulation of distinct MHC class II complex genes. In conclusion, DI not only abrogated the pro‐inflammatory effects of TLR stimulation but also targeted a specific metabolic vulnerability in CLL cells.This article is protected by copyright. All rights reserved

Toll‐like receptor 9 signaling in chronic lymphocytic leukemia cell lines

“…3C). As expected, the two groups of primary leukemic cells share an inflammatory response, but IkBz‐positive samples only show stress‐related and RNA metabolism signatures [19].…”

“…All the expressed genes were graphically represented with a Volcano plot that shows global perturbation of the transcriptomes, including up‐ and downregulated genes (Fig. 1B); as a comparison, we reported the same graph with previously analyzed data of primary CLL patients' samples, including IkBz‐high and IkBz‐low cases (GSE226904) [19]. Volcano plots show an overall increased number of DEGs, as genes with nominal P value < 0.01 and |Log 2 FC| ≥ 1, in IkBz‐high CpG samples as compared to both IkBz‐low and CLL cell lines.…”

“…However, no data are available on their TLR‐mediated signaling capabilities as compared to primary leukemic cells. To address this issue, we analyzed the transcriptomes of these three different cell lines treated in vitro with CpG, and we compared their gene expression profiles with that of primary CLL cells previously analyzed [19].…”

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

“…Moreover, it is a well-known inhibitor of the inflammatory NF-kB pathway and the STAT/JAK pathway [ 29 – 31 ]. Notably, it was recently shown that itaconate derivatives and DMF directly impact IkBz expression, blocking the inflammatory cascade induced by TLR4 in mouse macrophages [ 34 , 35 ]; moreover, DMF could inhibit the interaction and activation of the MyD88-IRAK4 signaling complex that mediates TLR signaling in plasmacytoid dendritic cells [ 36 ].…”