Work

Galectin-1 fuels monocyte hyperinflammation and is a novel therapeutic target in myeloproliferative neoplasms

Year: 2026

Type: article

Abstract: ABSTRACT: Dysregulation of galectins and global protein glycosylation has been reported in various cancers, but their role in myeloproliferative neoplasms (MPNs) remains incompletely understood. We performed single-cell RNA sequencing, which revealed significant enrichment of galectin genes in MPN monocytes. Cell-cell communication analysis predicted monocytes as a pivotal mediator of intercellular interactions and galectin signaling as a robust input/output pathway in monocytes. We identified elevated expression of galectin-1 (Gal-1, LGALS1) in monocytes from both human MPN samples and mouse models. Mass cytometry profiling of MPN blood samples demonstrated that recombinant Gal-1 (rGal-1) significantly increased levels of multiple inflammatory cytokines in monocytes without affecting other cell types. Incubation of CD14+ monocytes from patients with MPN with rGal-1 markedly increased the transcription and secretion of inflammatory cytokines. Mechanistically, we uncovered cross talk between the toll-like receptor 4 (TLR4) and Gal-1 signaling pathways, as evidenced by protein 3-dimensional modeling and coimmunoprecipitation analyses. Notably, TLR4 inhibition abrogated the Gal-1-mediated proinflammatory effects in monocytes. We further identified NF-κB-dependent signaling as a key downstream effector of Gal-1, as reporter assays demonstrated rGal-1-mediated activation of NF-κB signaling in a TLR4-dependent manner. We corroborated these findings in vivo in a murine model driven by MPLW515L, in which genetic abrogation of Lgals1 ameliorated key MPN disease features, including leukocytosis and splenomegaly. In addition, Gal-1 inhibition suppressed carrageenan-induced thrombosis and inflammation in vivo. In summary, we identify Gal-1 enrichment in MPN monocytes as a driver of monocyte-mediated inflammation through TLR4 and NF-κB activation and uncover a novel therapeutic avenue for MPNs.

Source: Blood

DOI: 10.1182/blood.2025032631