A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis

Rong Li, Michela Colombo, Guanlin Wang*, Antonio Rodriguez-Romera, Camelia Benlabiod, Natalie J Jooss, Jennifer O'Sullivan, Charlotte K Brierley, Sally-Ann Clark, Juan M Pérez Sáez, Pedro Aragón Fernández, Erwin M Schoof, Bo Porse, Yiran Meng, Abdullah O Khan, Sean Wen, Pengwei Dong, Wenjiang Zhou, Nikolaos Sousos, Lauren MurphyMatthew Clarke, Aude-Anais Olijnik, Zoë C Wong, Christina Simoglou Karali, Korsuk Sirinukunwattana, Hosuk Ryou, Ruggiero Norfo, Qian Cheng, Joana Carrelha, Zemin Ren, Supat Thongjuea, Vijay A Rathinam, Anandi Krishnan, Daniel Royston, Gabriel A Rabinovich, Adam J Mead*, Bethan Psaila*

*Corresponding author af dette arbejde

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.

OriginalsprogEngelsk
Artikelnummereadj7552
TidsskriftScience translational medicine
Vol/bind16
Udgave nummer768
Sider (fra-til)eadj7552
ISSN1946-6234
DOI
StatusUdgivet - 9 okt. 2024

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