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Inhibition of endosteal vascular niche remodeling rescues hematopoietic stem cell loss in AML

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Title: Inhibition of endosteal vascular niche remodeling rescues hematopoietic stem cell loss in AML
Authors: Lo Celso, C
Hawkins, ED
Akinduro, O
Duarte, D
Ang, H
De Filippo, K
Kong, I
Haltalli, M
Ruivo, N
Straszkowski, L
Vervoort, S
McLean, C
Weber, TS
Khorshed, R
Pirillo, C
Wei, A
Ramasamy, SK
Kusumbe, AP
Duffy, K
Adams, RH
Purton, LP
Carlin, LM
Item Type: Journal Article
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.
Issue Date: 21-Dec-2017
Date of Acceptance: 6-Nov-2017
URI: http://hdl.handle.net/10044/1/53606
DOI: https://dx.doi.org/10.1016/j.stem.2017.11.006
ISSN: 1875-9777
Publisher: Elsevier (Cell Press)
Start Page: 64
End Page: 77.e6
Journal / Book Title: Cell Stem Cell
Volume: 22
Issue: 1
Copyright Statement: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Sponsor/Funder: Cancer Research UK
Human Frontier Science Program
Bloodwise
Commission of the European Communities
European Hematology Association
Biotechnology and Biological Sciences Research Council (BBSRC)
Wellcome Trust
Wellcome Trust
Bloodwise
Wellcome Trust
Funder's Grant Number: 11831
rgp0051/2011
12033
337066
n/a
BB/L023776/1
105398/Z/14/Z
201356/Z/16/Z
15031
202300/Z/16/Z
Keywords: acute myeloid leukemia
blood vessels
bone marrow
endosteum
hematopoietic stem cells
intravital microscopy
microenvironment
osteoblasts
transendothelial migration
06 Biological Sciences
11 Medical And Health Sciences
Developmental Biology
Publication Status: Published
Appears in Collections:Clinical Sciences
Molecular Sciences
Faculty of Medicine
Faculty of Natural Sciences



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