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

Duarte, D. et al. (2018) Inhibition of endosteal vascular niche remodeling rescues hematopoietic stem cell loss in AML. Cell Stem Cell, 22(1), 64-77.e6. (doi: 10.1016/j.stem.2017.11.006) (PMID:29276143) (PMCID:PMC5766835)

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: Articles
• Additional Information: 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/I004033/1), 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/PO2209X/1). S.J.V. was funded by a Rubicon fellowship from the Netherlands Organization for Scientific Research.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Carlin, Dr Leo
• Authors: Duarte, D., Hawkins, E. D., Akinduro, O., Ang, H., De Filippo, K., Kong, I. Y., Haltalli, M., Ruivo, N., Straszkowski, L., Vervoot, S. J., McLean, C., Weber, T. S., Korshed, R., Pirillo, C., Wei, A., Ramasamy, S. K., Kusumbe, A. P., Duffy, K., Adams, R. H., Purton, L. E., Carlin, L. M., and Lo Celso, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Stem Cell
• Publisher: Elsevier (Cell Press)
• ISSN: 1934-5909
• ISSN (Online): 1875-9777
• Published Online: 21 December 2017
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Cell Stem Cell 22(1): 64-77.e6
• Publisher Policy: Reproduced under a Creative Commons License