Dimethyl Itaconate selectively targets chronic lymphocytic leukemia cells

ABSTRACT: Chronic Lymphocytic Leukemia (CLL) is strictly dependent on the complex interplay between the intrinsic features of the leukemic cells and microenvironmental stimulations including inflammatory stimuli by Toll Like Receptors (TLR) which protect CLL cells from drug induced apoptosis by upregulating NFKBIZ, an atypical co-transcription factor. To face the challenge of targeting transcription factors, we exploited the capacity of Dimethyl Itaconate (DI), an electrophilic synthetic derivative of Itaconate, to block NFKBIZ acting as anti-inflammatory agent. Primary CLL cells isolated from the peripheral blood of patients, leukemic splenocytes isolated from TCL1 transgenic mice, and circulating leukocytes isolated from healthy donors were treated in vitro with increasing concentrations of DI either alone or in combination with the TLR ligands. DI abrogated the induction of NFKBIZ as well as its target genes IL6 and IL10. Remarkably, DI reduced metabolic activation and cell viability of leukemic cells even if added after a robust TLR pre-stimulation; in contrast, no toxic effect was evident in normal leukocytes including T- and B-lymphocytes. DI induced apoptosis of malignant cells by reducing BCL-XL and MCL1 levels while inducing PARP cleavage. RNA sequencing highlighted that DI abrogated the TLR9-mediated upregulation of transcripts related to the metabolism of rRNAs, interferon and cytokine signaling. Notably, 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 vulnerability in CLL cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226904 | GEO | 2023/09/19

REPOSITORIES: GEO