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Myeloproliferative neoplasms are stem cell–driven cancers associated with a large burden of morbidity and mortality. Most patients present with early-stage disease, but a substantial proportion progress to myelofibrosis or secondary leukemia, advanced cancers with a poor prognosis and high symptom burden. Currently, it remains difficult to predict progression, and therapies that reliably prevent or reverse fibrosis are lacking. A major bottleneck to the discovery of disease-modifying therapies has been an incomplete understanding of the interplay between perturbed cellular and molecular states. Several cell types have individually been implicated, but a comprehensive analysis of myelofibrotic bone marrow is lacking. We therefore mapped the cross-talk between bone marrow cell types in myelofibrotic bone marrow. We found that inflammation and fibrosis are orchestrated by a "quartet" of immune and stromal cell lineages, with basophils and mast cells creating a TNF signaling hub, communicating with megakaryocytes, mesenchymal stromal cells, and proinflammatory fibroblasts. We identified the β-galactoside–binding protein galectin-1 as a biomarker of progression to myelofibrosis and poor survival in multiple patient cohorts and as a promising therapeutic target, with reduced myeloproliferation and fibrosis in vitro and in vivo and improved survival after galectin-1 inhibition. In human bone marrow organoids, TNF increased galectin-1 expression, suggesting a feedback loop wherein the proinflammatory myeloproliferative neoplasm clone creates a self-reinforcing niche, fueling progression to advanced disease. This study provides a resource for studying hematopoietic cell–niche interactions, with relevance for cancer-associated inflammation and disorders of tissue fibrosis. Editor's summary: Myeloproliferative neoplasms can transition to advanced cancers with poor prognosis. Predicting progression and reversing the associated myelofibrosis remain difficult. Li, Colombo, and Wang et al. present a mouse cancer-stroma interactome for myelofibrosis and show that galectin-1 is a potential inflammation-related target for treating disease. Mesenchymal stem cells, eosinophils, basophils, and mast cells were each implicated in an inflammatory niche that drove myelofibrosis progression. Inhibiting galectin-1 with a monoclonal antibody in a mouse model of myeloproliferative neoplasm decreased fibrosis and cell proliferation and had a beneficial effect on survival. Galectin-1 was associated with myelofibrosis and poor survival in multiple human cohorts. These results suggest that galectin-1 may be a target to alter the inflammatory niche and to reduce fibrosis in myeloproliferative neoplasms. —Brandon Berry [ABSTRACT FROM AUTHOR]