Altered Vasculature in Bone Marrow Drives Leukemogenesis

Acute myeloid leukemia (AML) has been associated with increased microvasculature and production of proangiogenic factors such as VEGF, but anti-VEGF therapies have not been clinically efficacious. To identify potentially targetable interactions between the bone marrow (BM) microenvironment and AML, Passaro and colleagues performed intravital two-photon microscopy to characterize the BM vasculature during engraftment of AML patient-derived xenografts (PDX). AML engraftment resulted in the expansion of the endothelial compartment and an increased density of structurally abnormal microvessels, increased hypoxia, and the presence of altered sinusoidal structures. Similarly, intravital microscopy of fluorescently labeled AML cell lines or patient-derived AML samples demonstrated that AML engraftment results in increased vascular permeability in the BM. Treatment of mice harboring AML PDXs with cytarabine, a standard chemotherapy for AML, decreased AML burden but did not decrease vascular permeability or the endothelial compartment. RNA sequencing identified an AML engraftment–associated transcriptomic signature in endothelial cells that was enriched for genes associated with angiogenesis and hypoxia response, including Nox4. Increases in Nox4 activate endothelial NOS3 and promote the release of nitric oxide (NO), and AML-engrafted immunodeficient mice as well primary AML samples exhibited increased NO levels. Nos3^−/− mice engrafted with murine AML exhibited delayed AML engraftment compared to wild-type mice, and cytarabine treatment further reduced AML engraftment in Nos3^−/−mice. The combination of NOS inhibitor and cytarabine treatment extended the remission-like phase and reduced leukemic progression, NOS3 activation, vascular leakiness, and hypoxia in mice engrafted with human AML compared with cytarabine alone. In parallel, AML engraftment resulted in the mobilization of ROS⁺ hematopoietic stem/progenitor cells to the periphery and the depletion of the residual normal hematopoietic stem cell (HSC) pool in the BM; treatment with NOS inhibitors and cytarabine increased residual normal HSC in the BM of mice engrafted with AML compared with cytarabine monotherapy. These findings describe the bone marrow vasculature in AML and suggest potential therapeutic strategies.

Passaro D, Di Tullio A, Abarrategi A, Rouault-Pierre K, Foster K, Ariza-McNaughton L, et al. Increased vascular permeability in the bone marrow microenvironment contributes to disease progression and drug response in acute myeloid leukemia. Cancer Cell 2017 Aug 31 [Epub ahead of print].

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