Journal
CANCER CELL
Volume 32, Issue 3, Pages 324-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2017.08.001
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Funding
- EHA
- Francis Crick Institute
- Cancer Research UK [FC001045]
- UK Medical Research Council [FC001045]
- Welcome Trust [FC001045]
- Cancer Research UK [15692] Funding Source: researchfish
- The Francis Crick Institute [10483, 10452, 10045, 10002] Funding Source: researchfish
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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.
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