Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia.,Cancer Cell

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Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia.
Cancer Cell ( IF 48.8 ) Pub Date : 2017-09-11 , DOI: 10.1016/j.ccell.2017.08.001
Diana Passaro ₁ , Alessandro Di Tullio ₁ , Ander Abarrategi ₁ , Kevin Rouault-Pierre ₁ , Katie Foster ₁ , Linda Ariza-McNaughton ₁ , Beatriz Montaner ₁ , Probir Chakravarty ₂ , Leena Bhaw ₃ , Giovanni Diana ₄ , François Lassailly ₁ , John Gribben ₅ , Dominique Bonnet ₁

Affiliation

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：

骨髓微环境中血管通透性的增加有助于急性髓系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受到骨髓（BM）微环境改变的主动串扰的影响。在本研究中，我们使用活体双光子显微镜提供了急性髓系白血病的骨髓脉管系统的详细图片。我们发现患者来源的异种移植物（PDX）的血管结构和功能存在一些异常，例如血管渗漏和缺氧加剧。内皮细胞转录组分析发现，一氧化氮 (NO) 是 PDX 和患者活检中这种表型的主要介质。此外，诱导化疗未能恢复正常脉管系统与预后不良相关。抑制 NO 产生可降低血管通透性，保留正常的造血干细胞功能，并改善 PDX 的治疗反应。

更新日期：2017-09-04

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