TY - JOUR
T1 - A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis
AU - Li, Rong
AU - Colombo, Michela
AU - Wang, Guanlin
AU - Rodriguez-Romera, Antonio
AU - Benlabiod, Camelia
AU - Jooss, Natalie J
AU - O'Sullivan, Jennifer
AU - Brierley, Charlotte K
AU - Clark, Sally-Ann
AU - Pérez Sáez, Juan M
AU - Fernández, Pedro Aragón
AU - Schoof, Erwin M
AU - Porse, Bo
AU - Meng, Yiran
AU - Khan, Abdullah O
AU - Wen, Sean
AU - Dong, Pengwei
AU - Zhou, Wenjiang
AU - Sousos, Nikolaos
AU - Murphy, Lauren
AU - Clarke, Matthew
AU - Olijnik, Aude-Anais
AU - Wong, Zoë C
AU - Karali, Christina Simoglou
AU - Sirinukunwattana, Korsuk
AU - Ryou, Hosuk
AU - Norfo, Ruggiero
AU - Cheng, Qian
AU - Carrelha, Joana
AU - Ren, Zemin
AU - Thongjuea, Supat
AU - Rathinam, Vijay A
AU - Krishnan, Anandi
AU - Royston, Daniel
AU - Rabinovich, Gabriel A
AU - Mead, Adam J
AU - Psaila, Bethan
PY - 2024/10/9
Y1 - 2024/10/9
N2 - 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.
AB - 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.
KW - Humans
KW - Stem Cell Niche
KW - Primary Myelofibrosis/metabolism
KW - Galectin 1/metabolism
KW - Inflammation/pathology
KW - Animals
KW - Bone Marrow/pathology
KW - Signal Transduction
KW - Mice
KW - Disease Progression
UR - http://www.scopus.com/inward/record.url?scp=85205994283&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.adj7552
DO - 10.1126/scitranslmed.adj7552
M3 - Journal article
C2 - 39383242
SN - 1946-6234
VL - 16
SP - eadj7552
JO - Science translational medicine
JF - Science translational medicine
IS - 768
M1 - eadj7552
ER -