The biological and clinical behaviors of hematological malignancies can be influenced by the active crosstalk with an altered bone marrow (BM) microenvironment. In the present study, we provide a detailed picture of the BM vasculature in acute myeloid leukemia using intravital two-photon microscopy. We found several abnormalities in the vascular architecture and function in patient-derived xenografts (PDX), such as vascular leakiness and increased hypoxia. Transcriptomic analysis in endothelial cells identified nitric oxide (NO) as major mediator of this phenotype in PDX and in patient-derived biopsies. Moreover, induction chemotherapy failing to restore normal vasculature was associated with a poor prognosis. Inhibition of NO production reduced vascular permeability, preserved normal hematopoietic stem cell function, and improved treatment response in PDX.

中文翻译：

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骨髓微环境中增加的血管通透性有助于急性髓性白血病的疾病进展和药物反应。

血液恶性肿瘤的生物学和临床行为可能会受到与改变的骨髓 (BM) 微环境的主动串扰的影响。在本研究中，我们使用活体双光子显微镜提供了急性髓性白血病中 BM 脉管系统的详细图片。我们在患者来源的异种移植物 (PDX) 中发现了一些血管结构和功能异常，例如血管渗漏和缺氧增加。内皮细胞的转录组学分析确定一氧化氮 (NO) 是 PDX 和患者衍生活检中这种表型的主要介质。此外，未能恢复正常脉管系统的诱导化疗与预后不良有关。抑制 NO 产生会降低血管通透性，保持正常的造血干细胞功能，