Passaro, D;
Di Tullio, A;
Abarrategi, A;
Rouault-Pierre, K;
Foster, K;
Ariza-McNaughton, L;
Montaner, B;
... Bonnet, D; + view all
(2017)
Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia.
Cancer Cell
, 32
(3)
324-341.e6.
10.1016/j.ccell.2017.08.001.
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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.
| Type: | Article |
|---|---|
| Title: | Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ccell.2017.08.001 |
| Publisher version: | https://doi.org/10.1016/j.ccell.2017.08.001 |
| Language: | English |
| Additional information: | © 2017 The Francis Crick Institute. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | NOS inhibitors, acute myeloid leukemia, chemotherapy, endothelial cells, hematopoietic stem cells, hypoxia, intravital 2P microscopy, microenvironment, nitric oxide, vascular permeability, Animals, Antineoplastic Agents, Bone Marrow, Capillary Permeability, Cellular Microenvironment, Disease Progression, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Hematopoietic Stem Cells, Humans, Leukemia, Myeloid, Acute, Mice, Neoplasm Transplantation, Nitric Oxide, Treatment Outcome |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10045751 |
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