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 b...
| Egile Nagusiak: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formatua: | Journal article |
| Hizkuntza: | English |
| Argitaratua: |
American Association for the Advancement of Science
2024
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| _version_ | 1826315397931991040 |
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| author | Li, R Colombo, M Wang, G Rodriguez-Romera, A Benlabiod, C Jooss, NJ O'Sullivan, J Brierley, CK Clark, S-A 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, A-A 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 |
| author_facet | Li, R Colombo, M Wang, G Rodriguez-Romera, A Benlabiod, C Jooss, NJ O'Sullivan, J Brierley, CK Clark, S-A 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, A-A 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 |
| author_sort | Li, R |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-12-09T03:24:38Z |
| format | Journal article |
| id | oxford-uuid:f677af36-04db-4060-b82b-c814c4f1a1c6 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:24:38Z |
| publishDate | 2024 |
| publisher | American Association for the Advancement of Science |
| record_format | dspace |
| spelling | oxford-uuid:f677af36-04db-4060-b82b-c814c4f1a1c62024-11-26T10:06:53ZA proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f677af36-04db-4060-b82b-c814c4f1a1c6EnglishSymplectic ElementsAmerican Association for the Advancement of Science2024Li, RColombo, MWang, GRodriguez-Romera, ABenlabiod, CJooss, NJO'Sullivan, JBrierley, CKClark, S-APérez Sáez, JMFernández, PASchoof, EMPorse, BMeng, YKhan, AOWen, SDong, PZhou, WSousos, NMurphy, LClarke, MOlijnik, A-AWong, ZCKarali, CSSirinukunwattana, KRyou, HNorfo, RCheng, QCarrelha, JRen, ZThongjuea, SRathinam, VAKrishnan, ARoyston, DRabinovich, GAMead, AJPsaila, BMyeloproliferative 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. |
| spellingShingle | Li, R Colombo, M Wang, G Rodriguez-Romera, A Benlabiod, C Jooss, NJ O'Sullivan, J Brierley, CK Clark, S-A 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, A-A 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 A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis |
| title | A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis |
| title_full | A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis |
| title_fullStr | A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis |
| title_full_unstemmed | A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis |
| title_short | A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis |
| title_sort | proinflammatory stem cell niche drives myelofibrosis through a targetable galectin 1 axis |
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