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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: 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
Bloodwise
Commission of the European Communities
European Hematology Association
Biotechnology and Biological Sciences Research Council (BBSRC)
Wellcome Trust
Wellcome Trust
Blood Cancer UK
Human Frontier Science Program
Wellcome Trust
Biotechnology and Biological Sciences Research Council (BBSRC)
Biotechnology and Biological Sciences Research Council (BBSRC)
Medical Research Council (MRC)
Funder's Grant Number: 11831
12033
337066
n/a
BB/L023776/1
105398/Z/14/Z
201356/Z/16/Z
15031
rgp0051/2011
202300/Z/16/Z
BB/I004033/1
BB/K021168/1
MR/M01245X/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell & Tissue Engineering
Cell Biology
ACUTE MYELOID-LEUKEMIA
BONE-MARROW NICHE
C-X-C
INCREASED ANGIOGENESIS
ENDOTHELIAL-CELLS
MICROSCOPY DATA
GRO-BETA
IN-VIVO
DIFFERENTIATION
OSTEOGENESIS
acute myeloid leukemia
blood vessels
bone marrow
endosteum
hematopoietic stem cells
intravital microscopy
microenvironment
osteoblasts
transendothelial migration
Animals
Bone Marrow
Cell Count
Hematopoiesis
Hematopoietic Stem Cells
Humans
Intravital Microscopy
Leukemia, Myeloid, Acute
Mice, Inbred C57BL
Spleen
Stem Cell Niche
Stromal Cells
Time Factors
Tumor Microenvironment
Spleen
Hematopoietic Stem Cells
Stromal Cells
Bone Marrow
Animals
Mice, Inbred C57BL
Humans
Cell Count
Hematopoiesis
Time Factors
Leukemia, Myeloid, Acute
Stem Cell Niche
Tumor Microenvironment
Intravital Microscopy
Developmental Biology
06 Biological Sciences
11 Medical and Health Sciences
Publication Status: Published
Online Publication Date: 2017-12-21
Appears in Collections:National Heart and Lung Institute
Institute of Clinical Sciences
Faculty of Medicine
Faculty of Natural Sciences