Editors' ChoiceCancer

Just say NO to leaky bone marrow vasculature in AML

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Science Translational Medicine  04 Oct 2017:
Vol. 9, Issue 410, eaap8163
DOI: 10.1126/scitranslmed.aap8163


Inhibition of nitric oxide (NO) production improved treatment response and normalized NO-mediated alterations in bone marrow vascular architecture and function in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive hematologic cancer characterized by occurrence of mutations in hematopoietic stem and progenitor cells, expansion of dysfunctional immature myeloid cells, and poor outcomes related to therapy resistance and relapse. AML cells are capable of altering the bone marrow (BM) microenvironment, including the vasculature, creating a receptive environment for leukemic cells to arise, expand, and develop resistance to therapy. The mechanisms by which AML cells modify BM vascular architecture and structural integrity to promote leukemogenesis and progression are not well described.

Passaro et al. used intravital two-photon microscopy for functional and dynamic imaging of the BM niche in patient-derived xenograft (PDX) mouse models to provide a detailed picture of the vasculature in AML. Human AML engraftment altered BM vascular architecture and function, including expansion of endothelial cells (EC), increased microvascular density and widespread increases in BM hypoxia. Furthermore, AML engraftment increased BM vascular permeability that persisted despite significant reductions in leukemic engraftment after chemotherapy. Transcriptome analysis demonstrated that AML-induced BM microenvironment changes activated proangiogenic pathways in BM-derived ECs and increased expression of Nox4, a gene involved in the response to hypoxia through activation of nitric oxide synthetase 3 (NOS3) and release of nitric oxide (NO). Accordingly, there was an AML-induced overproduction of NO, a key mediator of vascular permeability, by abnormally activated NOS3 in BM ECs both prior to and after chemotherapy. Inhibition of NO production with a NOS inhibitor improved vascular function and response to chemotherapy. Moreover, NOS inhibition restored normal BM vascular niche activity and improved residual normal hematopoietic stem cell (HSC) function and ability to outcompete leukemia cells.

These results confirm that AML induces hypoxia and angiogenesis and modifies the BM microenvironment vascular architecture, permeability, and function through activation of hypoxia-responsive NOX4-NOS3-NO pathways. These changes contribute to chemotherapy resistance, impaired HSC function, and AML relapse. The observation that NOS inhibition can abrogate AML-induced BM vascular niche changes and improve response to chemotherapy suggest that clinical trials combining chemotherapy with NOS inhibitors, or other approaches targeting NO production and vascular permeability, could lead to improved outcomes for patients with AML. This study provides strong rationale for further research to develop novel approaches targeting the abnormal BM vascular niche in AML.

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