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

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

Author information

1
Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
2
Bioinformatic Core Unit, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
3
Advanced Sequencing Unit, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
4
MRC Centre for Developmental Neurobiology, King's College London, London, UK.
5
Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
6
Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address: dominique.bonnet@crick.ac.uk.

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.

KEYWORDS:

NOS inhibitors; acute myeloid leukemia; chemotherapy; endothelial cells; hematopoietic stem cells; hypoxia; intravital 2P microscopy; microenvironment; nitric oxide; vascular permeability

PMID:
28870739
PMCID:
PMC5598545
DOI:
10.1016/j.ccell.2017.08.001
[Indexed for MEDLINE]
Free PMC Article

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