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.

中文翻译：

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促炎干细胞生态位通过可靶向的半乳糖凝集素-1 轴驱动骨髓纤维化


骨髓增生性肿瘤是干细胞驱动的癌症，与发病率和死亡率的高负担有关。大多数患者表现为早期疾病，但很大一部分进展为骨髓纤维化或继发性白血病，即预后不良和症状负担高的晚期癌症。目前，仍然难以预测进展，并且缺乏能够可靠地预防或逆转纤维化的疗法。发现疾病修饰疗法的一个主要瓶颈是对受扰动的细胞状态和分子状态之间的相互作用的理解不完整。几种细胞类型单独涉及，但缺乏对骨髓纤维化骨髓的全面分析。因此，我们绘制了骨髓纤维化骨髓中骨髓细胞类型之间的串扰。我们发现炎症和纤维化是由免疫细胞和基质细胞谱系的“四重奏”精心策划的，嗜碱性粒细胞和肥大细胞形成 TNF 信号枢纽，与巨核细胞、间充质基质细胞和促炎成纤维细胞通讯。我们确定 β-半乳糖苷结合蛋白半乳糖凝集素-1 是多个患者队列中进展为骨髓纤维化和生存率低的生物标志物，并且是一个有前途的治疗靶点，在体外和体内减少了骨髓增殖和纤维化，并在半乳糖凝集素-1 抑制后提高了生存率。在人骨髓类器官中，TNF 增加了半乳糖凝集素-1 的表达，表明存在一个反馈回路，其中促炎性骨髓增生性肿瘤克隆创造了一个自我强化的生态位，从而促进了向晚期疾病的进展。本研究为研究造血细胞-生态位相互作用提供了资源，与癌症相关炎症和组织纤维化疾病有关。