Although vascular density and vascular endothelial growth factor (VEGF) levels are increased in acute myeloid leukaemia (AML), anti-VEGF therapy has been ineffective in clinical trials. Mainly studied in vitro, the crosstalk between leukaemic cells and endothelial cells (ECs) remains poorly understood. Using two-photon microscopy, a new study has investigated the bone marrow vasculature in AML in vivo. Engraftment of patient-derived AML cells into mice increased vascular permeability compared with control mice engrafted with normal human haematopoietic stem and/or progenitor cells, an effect that persisted after treatment with the AML chemotherapy cytarabine. Interestingly, the NAPDH oxidase Nox4 was the most upregulated common gene in bone marrow-derived ECs of AML-engrafted mice, and was associated with high production of reactive oxygen species in the bone marrow as well as induction of nitric oxide (NO) synthase 3 (NOS3) in ECs. Accordingly, levels of NO, an inducer of vascular permeability, in the bone marrow of AML-engrafted mice were increased compared with control mice. Pharmacological NOS inhibition in combination with cytarabine-reduced AML progression and vascular permeability in the mice, providing evidence for a potential clinical benefit of targeting NOS in the bone marrow vascular niche in AML.
References
Passaro, D. et al. Increased vascular permeability in the bone marrow microenvironment contributes to disease progression and drug response in acute myeloid leukemia. Cancer Cell 32, 324–341 (2017)
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Harjes, U. The real deal. Nat Rev Cancer 17, 575 (2017). https://doi.org/10.1038/nrc.2017.89
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DOI: https://doi.org/10.1038/nrc.2017.89