B cell receptor-mediated amplification of the interferon response in CLL cells

ABSTRACT: Abstract Chronic lymphocytic leukemia (CLL) comprises biologically distinct subtypes that differ in prognostic behavior and B cell receptor (BCR) signaling activity. We previously showed that unmutated CLL (U-CLL) cells exhibit enhanced type I interferon (IFN) responses, but the downstream effectors and signaling mechanisms remain incompletely defined. In the present study, we investigated regulation of the interferon-stimulated gene lymphocyte activation gene 3 (LAG3) in primary CLL cells and its relationship to clinical subtype, MYC activity and BCR signaling. LAG3 expression was generally low at baseline but was robustly induced by IFN in a highly variable, patient-specific manner. Elevated IFN-induced LAG3 expression was associated with U-CLL, higher MYC activity and inferior overall survival, suggesting that it marks a more aggressive disease state. Bioinformatic analyses of primary CLL datasets and in vitro experiments indicated that high-LAG3 responses were linked to transcriptional signatures of active BCR signaling. IFN increased c-MYC and LAG3 expression in CLL cells and pharmacologic MYC inhibition reduced both responses. Mechanistically, IFN promoted association of ZAP70 with the IFNAR complex and inhibition of ZAP70 or multiple BCR-pathway components suppressed IFN-induced LAG3 expression. Moreover, BCR activation amplified IFN-driven LAG3 expression in normal B cells and in CLL cells, whereas BTK inhibition reduced LAG3 expression in patient samples in vivo. These findings support a model in which IFN signaling is rewired in aggressive CLL through cooperation with BCR-associated pathways to promote MYC-dependent LAG3 expression. This crosstalk may contribute to disease progression and helps explain a potential mechanism by which BCR-directed therapies attenuate pathogenic IFN responses in CLL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE329311 | GEO | 2026/05/15

REPOSITORIES: GEO