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.
Functional imaging of the BM vascular niche using intravital 2P microscopy
Increased vascular permeability is caused by robust molecular alterations in ECs
Persistent high NO after chemotherapy is associated with poor prognosis in patients
Inhibition of EC-derived NO normalizes vasculature and improve response to Ara.C
Passaro et al. show that acute myeloid leukemia, mainly via nitric oxide (NO), causes bone marrow vascular abnormalities and that failure to restore normal vasculature after induction chemotherapy is associated with a poor prognosis. Importantly, inhibition of NO production improves treatment response in vivo.