Galectin-1 Fuels Monocyte Hyperinflammation and Represents a Novel Therapeutic Target in Myeloproliferative Neoplasms

Abstract

Dysregulation of galectins and global protein glycosylation have been reported in various cancers, but their role in myeloproliferative neoplasms (MPNs) have remained incompletely understood. We performed single-cell RNA sequencing (scRNA-seq) which revealed significant enrichment of galectin genes in MPN monocytes. Cell-cell communication analysis predicted monocytes as a pivotal mediator of cell interactions and galectin signaling as a robust input/output pathway for monocytes. We identified elevated expression of galectin-1 (Gal-1, LGALS1) in monocytes from both human MPN samples and mouse models. Mass cytometry (CyTOF) profiling of MPN blood samples demonstrated that recombinant galectin-1 (rGal-1) significantly increased levels of multiple inflammatory cytokines in monocytes without affecting other cell types. Incubation of CD14+ monocytes from MPN patients with rGal-1 led to markedly increased transcription and secretion of inflammatory cytokines. Mechanistically, we uncovered crosstalk between the TLR4 and Gal-1 signaling pathways, as evidenced by protein 3D modeling and co-immunoprecipitation. Notably, TLR4 inhibition abrogated 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. Additionally, 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.