Increased vascular permeability in the bone marrow microenvironment contributes to disease progression and drug response in acute myeloid leukemia
journal contributionposted on 2020-10-15, 16:24 authored by Diana Passaro, Alessandro Di Tullio, Ander Abarrategi, Kevin Rouault-Pierre, Katie Foster, Linda Ariza-McNaughton, Beatriz Montaner, Probir Chakravarty, Leena Bhaw, Giovanni Diana, François Lassailly, John Gribben, Dominique Bonnet
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.
NOS inhibitorsacute myeloid leukemiachemotherapyendothelial cellshematopoietic stem cellshypoxiaintravital 2P microscopymicroenvironmentnitric oxidevascular permeabilityAnimalsAntineoplastic AgentsBone MarrowCapillary PermeabilityCellular MicroenvironmentDisease ProgressionGene Expression ProfilingGene Expression Regulation, LeukemicHematopoietic Stem CellsHumansLeukemia, Myeloid, AcuteMiceNeoplasm TransplantationNitric OxideTreatment OutcomeBonnet FC001045CBASBRF-ackFC-ackLM-ack1112 Oncology and Carcinogenesis1109 NeurosciencesOncology & Carcinogenesis