骨髓增生性肿瘤是干细胞驱动的癌症，具有较高的发病率和死亡率。大多数患者出现早期疾病，但相当一部分进展为骨髓纤维化或继发性白血病、晚期癌症，预后不良且症状负担高。目前，预测进展仍然很困难，并且缺乏可靠预防或逆转纤维化的疗法。发现疾病缓解疗法的一个主要瓶颈是对扰动的细胞和分子状态之间的相互作用的不完全理解。几种细胞类型都被单独涉及，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和基质细胞谱系的“四重奏”精心策划的，其中嗜碱性粒细胞和肥大细胞创建了 TNF 信号中枢，与巨核细胞、间充质基质细胞和促炎成纤维细胞进行通信。我们确定了 β-半乳糖苷结合蛋白 galectin-1 作为多个患者队列中骨髓纤维化进展和生存不良的生物标志物，并且作为一个有前途的治疗靶点，在体外和体内减少骨髓增殖和纤维化，并提高 galectin-1 后的生存率抑制。在人骨髓类器官中，TNF 增加了半乳糖凝集素 1 的表达，这表明促炎性骨髓增殖性肿瘤克隆存在一个反馈循环，其中创建了一个自我强化的生态位，从而促进了晚期疾病的进展。这项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相关。

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.