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

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.