A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis
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.
Authors
- Camélia Benlabiod (ORCID: https://orcid.org/0000-0001-7119-9326)
- Jennifer O’Sullivan (ORCID: https://orcid.org/0000-0003-0502-7133)
- Nikolaos Sousos (ORCID: https://orcid.org/0000-0002-9100-2954)
- Hosuk Ryou (ORCID: https://orcid.org/0000-0001-6450-0117)
- Anandi Krishnan (ORCID: https://orcid.org/0000-0002-0962-2215)
- Supat Thongjuea (ORCID: https://orcid.org/0000-0002-9129-4694)
- Pedro Aragon-Fernandez (ORCID: https://orcid.org/0000-0002-9372-8265)
- Vijay Rathinam (ORCID: https://orcid.org/0000-0002-8009-3977)
- Pengwei Dong (ORCID: https://orcid.org/0000-0002-6359-4219)
- Erwin M. Schoof (ORCID: https://orcid.org/0000-0002-3117-7832)
- M. Colombo (ORCID: https://orcid.org/0000-0003-2252-1424)
- Zoë C. Wong (ORCID: https://orcid.org/0000-0001-6006-1233)
- Daniel Royston (ORCID: https://orcid.org/0000-0002-5151-2378)
- Gabriel A. Rabinovich (ORCID: https://orcid.org/0000-0002-0947-8735)
- Charlotte Brierley (ORCID: https://orcid.org/0000-0002-4028-3733)
- Sally‐Ann Clark (ORCID: https://orcid.org/0000-0003-1720-7975)
- Adam J. Mead (ORCID: https://orcid.org/0000-0001-8522-1002)
- Aude-Anaïs Olijnik (ORCID: https://orcid.org/0000-0002-0980-6663)
- Natalie J. Jooss (ORCID: https://orcid.org/0000-0002-2314-4993)
- Yiran Meng (ORCID: https://orcid.org/0000-0002-9333-2383)
- Ruggiero Norfo (ORCID: https://orcid.org/0000-0002-9485-6285)
- Abdullah O. Khan (ORCID: https://orcid.org/0000-0003-0825-3179)
- Bo Porse (ORCID: https://orcid.org/0000-0001-6043-0844)
- Korsuk Sirinukunwattana (ORCID: https://orcid.org/0000-0002-3603-4435)
- Juan M. Pérez‐Sáez (ORCID: https://orcid.org/0000-0002-6722-5760)
- Zemin Ren
- Bethan Psaila (ORCID: https://orcid.org/0000-0001-8198-9663)
- Qian Cheng (ORCID: https://orcid.org/0000-0001-6063-6922)
- Lauren C. Murphy (ORCID: https://orcid.org/0000-0001-9506-2762)
- Guanlin Wang (ORCID: https://orcid.org/0000-0002-5622-3890)
- Christina Simoglou Karali (ORCID: https://orcid.org/0000-0003-2169-6580)
- Antonio Rodriguez-Romera (ORCID: https://orcid.org/0000-0001-7193-9144)
- Matthew Clarke (ORCID: https://orcid.org/0009-0003-2433-0485)
- Joana Carrelha (ORCID: https://orcid.org/0000-0002-0324-2617)
- Rong Li (ORCID: https://orcid.org/0000-0002-1805-810X)
- Sean Wen
- Wenjiang Zhou
Institutions
- Rutgers, The State University of New Jersey (US)
- Jiangnan University (CN)
- University of Modena and Reggio Emilia (IT)
- University of Copenhagen (DK)
- Fudan University (CN)
- Copenhagen University Hospital (DK)
- University of Oxford (GB)
- Shanghai FRP Research Institute (China) (CN)
- Ludwig Cancer Research (GB)
- MRC Weatherall Institute of Molecular Medicine (GB)
- Oxford Centre for Computational Neuroscience (GB)
- Human Technopole (IT)
- MRC Human Immunology Unit (GB)
- Oxford BioMedica (United Kingdom) (GB)
- Science Oxford (GB)
- Oxford University Hospitals NHS Trust (GB)
- Jenner Institute (GB)
- Imperial College London (GB)
- Fundación Ciencias Exactas y Naturales (AR)
- Experimental Medicine and Biology Institute (AR)
- UConn Health (US)
- University of Birmingham (GB)
- Technical University of Denmark (DK)
- Stanford University (US)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2024-10-09
- DOI
- https://doi.org/10.1126/scitranslmed.adj7552
- Citations
- 22
- Primary Topic
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 9.20
Funders
- Gilead Sciences
- Celgene
- Incyte
- Galecto
- Cancer Research UK
- National Institute for Health and Care Research
- Kay Kendall Leukaemia Fund
- University of Oxford
- Chinese Academy of Medical Sciences
- Blood Cancer UK
- Medical Research Council