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骨髓微环境中血管通透性增加促进急性髓系白血病的疾病进展和药物反应。

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

作者信息

Passaro Diana, Di Tullio Alessandro, Abarrategi Ander, Rouault-Pierre Kevin, Foster Katie, Ariza-McNaughton Linda, Montaner Beatriz, Chakravarty Probir, Bhaw Leena, Diana Giovanni, Lassailly François, Gribben John, Bonnet Dominique

机构信息

Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.

Bioinformatic Core Unit, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.

出版信息

Cancer Cell. 2017 Sep 11;32(3):324-341.e6. doi: 10.1016/j.ccell.2017.08.001. Epub 2017 Sep 1.

DOI:10.1016/j.ccell.2017.08.001
PMID:28870739
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5598545/
Abstract

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.

摘要

血液系统恶性肿瘤的生物学和临床行为会受到与改变的骨髓（BM）微环境之间活跃的相互作用的影响。在本研究中，我们使用活体双光子显微镜详细描绘了急性髓系白血病患者骨髓血管系统的情况。我们在患者来源的异种移植模型（PDX）中发现了血管结构和功能的若干异常，如血管渗漏和缺氧增加。对内皮细胞的转录组分析确定一氧化氮（NO）是PDX和患者活检样本中这种表型的主要介质。此外，诱导化疗未能恢复正常血管系统与预后不良相关。抑制NO生成可降低血管通透性，维持正常造血干细胞功能，并改善PDX中的治疗反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a58/5598545/6177aad89e6c/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a58/5598545/138a282c9a20/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a58/5598545/f1536ff651ea/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a58/5598545/11b9c9184bac/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a58/5598545/3a7a575a43ef/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a58/5598545/bd617bf822bf/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a58/5598545/95e13cd0d4cf/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a58/5598545/0aea784e01d1/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a58/5598545/6177aad89e6c/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a58/5598545/138a282c9a20/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a58/5598545/f1536ff651ea/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a58/5598545/11b9c9184bac/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a58/5598545/3a7a575a43ef/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a58/5598545/bd617bf822bf/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a58/5598545/95e13cd0d4cf/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a58/5598545/0aea784e01d1/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a58/5598545/6177aad89e6c/gr7.jpg

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