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    Inhibition of Endosteal Vascular Niche Remodeling Rescues Hematopoietic Stem Cell Loss in AML


    Duarte, Delfim and Hawkins, Edwin D. and Akinduro, Olufolake and Ang, Heather and De Filippo, Katia and Kong, Isabella Y. and Haltalli, Myriam and Ruivo, Nicola and Straszkowski, Lenny and Vervoort, Stephin J. and McLean, Catriona and Weber, Tom S. and Korshed, Reema and Pirillo, Chiara and Wei, Andrew and Ramasamy, Saravana K. and Kusumbe, Anjali P. and Duffy, Ken R. and Adams, Ralf H. and Purton, Louise E. and Carlin, Leo M. and Lo Celso, Christina (2018) Inhibition of Endosteal Vascular Niche Remodeling Rescues Hematopoietic Stem Cell Loss in AML. Cell Stem Cell, 22 (1). pp. 64-77. ISSN 1875-9777

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    Abstract

    Bone marrow vascular niches sustain hematopoietic stem cells (HSCs) and are drastically remodeled in leukemia to support pathological functions. Acute myeloid leukemia (AML) cells produce angiogenic factors, which likely contribute to this remodeling, but anti-angiogenic therapies do not improve AML patient outcomes. Using intravital microscopy, we found that AML progression leads to differential remodeling of vasculature in central and endosteal bone marrow regions. Endosteal AML cells produce pro-inflammatory and anti-angiogenic cytokines and gradually degrade endosteal endothelium, stromal cells, and osteoblastic cells, whereas central marrow remains vascularized and splenic vascular niches expand. Remodeled endosteal regions have reduced capacity to support non-leukemic HSCs, correlating with loss of normal hematopoiesis. Preserving endosteal endothelium with the small molecule deferoxamine or a genetic approach rescues HSCs loss, promotes chemotherapeutic efficacy, and enhances survival. These findings suggest that preventing degradation of the endosteal vasculature may improve current paradigms for treating AML.

    Item Type: Article
    Additional Information: This open access article is available under the terms of the Creative Commons Attribution License (CC BY). https://creativecommons.org/licenses/by/4.0/
    Keywords: acute myeloid leukemia; microenvironment; bone marrow; blood vessels; endosteum; osteoblasts; hematopoietic stem cells; transendothelial migration; intravital microscopy;
    Academic Unit: Faculty of Science and Engineering > Research Institutes > Hamilton Institute
    Item ID: 10165
    Identification Number: https://doi.org/10.1016/j.stem.2017.11.006
    Depositing User: Dr Ken Duffy
    Date Deposited: 01 Nov 2018 15:39
    Journal or Publication Title: Cell Stem Cell
    Publisher: Elsevier
    Refereed: Yes
    Funders: GABBA, European Haematology Association (EHA)-American Society of Hematology (ASH), Bloodwise, HFSP, CRUK, BBSRC, KKLF, European Research Council (ERC), EHA, Wellcome Trust, Medical Research Council, NHLI Foundation, Cancer Research UK
    URI:

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