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

Delfim Duarte; Edwin D Hawkins; Olufolake Akinduro; Heather Ang; Katia De Filippo; Isabella Y Kong; Myriam Haltalli; Nicola Ruivo; Lenny Straszkowski; Stephin J Vervoort; Catriona McLean; Tom S Weber; Reema Khorshed; Chiara Pirillo; Andrew Wei; Saravana K Ramasamy; Anjali P Kusumbe; Ken Duffy; Ralf H Adams; Louise E Purton; Leo M Carlin; Cristina Lo Celso

Journal article

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

Delfim Duarte, Edwin D Hawkins, Olufolake Akinduro, Heather Ang, Katia De Filippo, Isabella Y Kong, Myriam Haltalli, Nicola Ruivo, Lenny Straszkowski, Stephin J Vervoort, Catriona McLean, Tom S Weber, Reema Khorshed, Chiara Pirillo, Andrew Wei, Saravana K Ramasamy, Anjali P Kusumbe, Ken Duffy, Ralf H Adams, Louise E Purton Show all

CELL STEM CELL | CELL PRESS | Published : 2018

DOI: 10.1016/j.stem.2017.11.006

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 nich..

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University of Melbourne Researchers

Louise Purton Author Medicine - St Vincent's Hospital

Catriona McLean Author Florey Department of Neuroscience and Mental Health

Tom Weber Author Medical Biology (w.e.h.i.)

Edwin Hawkins Author Medical Biology (w.e.h.i.)

Grants

Awarded by GABBA PhD program (FCT fellowship)

Awarded by Royal Society

Awarded by European Research Council (ERC)

Awarded by KKLF

Awarded by ERC

Awarded by Medical Research Council

Awarded by Wellcome Trust

Awarded by Bloodwise

Awarded by BBSRC

Awarded by CRUK

Awarded by HFSP

Awarded by EHA

Awarded by Biotechnology and Biological Sciences Research Council

Awarded by Cancer Research UK

Awarded by Kennedy Trust

Funding Acknowledgements

D.D. was supported by the GABBA PhD program (FCT fellowship SFRH/BD/52195/2013) and by the European Haematology Association (EHA)-American Society of Hematology (ASH) Translational Research Training in Hematology (TRTH) program; C.L.C., by Bloodwise (12033), HFSP (RGP0051/2011), CRUK (C36195/A1183), BBSRC (BB/1004033/1), KKLF (KKL460), and European Research Council (ERC) (337066); E.D.H., by the EHA and Bloodwise (12033); K.D.F., by the Wellcome Trust (201356/Z/16/Z); L.M.C., by the Medical Research Council (MR/M01245X/1), the NHLI Foundation, and core funding from Cancer Research UK; and R.H.A., by ERC (AdG 339409 AngioBone). S.K.R. is a Sir Henry Dale Fellow jointly supported by the Wellcome Trust and the Royal Society (202300/Z/16/Z). A.P.K. is an MRC fellow (MR/P02209X/1). S.J.V. was funded by a Rubicon fellowship from the Netherlands Organization for Scientific Research. We are grateful to A. Medvinsky (U. of Edinburgh) for his kind gift of Flk1-GFP mice and to C. Nerlov for the Pu1-YFP mice. We thank D. Keller, S. Rothery (Imperial College FILM facility), and N. Sergent (Carl Zeiss) for support with microscopy; S. Piperelis, E. Ibarguen, W. Steel, H. Goyal, and C. Godfrey (Imperial College CBS facility) for logistical help; J. Srivastava, C. Simpson, and J. Rowley for support from the flow cytometry facility; Arwa Kocache (Imperial College Healthcare NHS Trust) for supplying cytarabine and doxorubicin; and R.E. Sinden, H. Fleming, K. Hodivala-Dilke, and R.W. Johnstone for critical reading of the manuscript.