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  • Title: A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis.
    Author: Li R, Colombo M, Wang G, Rodriguez-Romera A, Benlabiod C, Jooss NJ, O'Sullivan J, Brierley CK, Clark SA, Pérez Sáez JM, Fernández PA, Schoof EM, Porse B, Meng Y, Khan AO, Wen S, Dong P, Zhou W, Sousos N, Murphy L, Clarke M, Olijnik AA, Wong ZC, Karali CS, Sirinukunwattana K, Ryou H, Norfo R, Cheng Q, Carrelha J, Ren Z, Thongjuea S, Rathinam VA, Krishnan A, Royston D, Rabinovich GA, Mead AJ, Psaila B.
    Journal: Sci Transl Med; 2024 Oct 09; 16(768):eadj7552. PubMed ID: 39383242.
    Abstract:
    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.
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