IκBζ target genes in chronic lymphocytic leukemia.

IκBζ, an atypical IκB protein induced downstream of Toll-like receptor (TLR) signaling, is pivotal in orchestrating inflammatory responses and modulating inflammation-associated B cell malignancies. However, the transcriptional and epigenetic programs regulated by IκBζ in both normal and malignant B cells remain poorly described. Here, we analyzed chronic lymphocytic leukemia (CLL) cells by epigenomic profiling to dissect the molecular function of IκBζ in leukemia. In primary human B cells and CLL samples, chromatin immunoprecipitation sequencing (ChIP-seq) and cleavage under targets and tagmentation (CUT&Tag) analyses delineated a comprehensive genome-wide landscape of IκBζ binding sites. Key genes, including NFKB2, BATF, and FOXP1, gained IκBζ binding after TLR stimulation in both CLL and B cells, whereas CXCR5 was mainly bound in CLL cells. Pharmacological or genetic inhibition of IκBζ signaling disrupted the induction of these molecules, highlighting its potential role as a central transcriptional tuner that integrates TLR-mediated inflammatory pathways with B cell receptor (BCR) signaling and migration.