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HIF-1α is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1α
Forristal, C. E. Nowlan, B. Jacobsen, R. N. Barbier, V. Walkinshaw, G. Walkley, Carl Winkler, I. G. Levesque, J. P.
Forristal, C. E.
Nowlan, B.
Jacobsen, R. N.
Barbier, V.
Walkinshaw, G.
Walkley, Carl
Winkler, I. G.
Levesque, J. P.
Abstract
Many patients with hematological neoplasms fail to mobilize sufficient numbers of hematopoietic stem cells (HSCs) in response to granulocyte colony-stimulating factor (G-CSF) precluding subsequent autologous HSC transplantation. Plerixafor, a specific antagonist of the chemokine receptor CXCR4, can rescue some but not all patients who failed to mobilize with G-CSF alone. These refractory poor mobilizers cannot currently benefit from autologous transplantation. To discover alternative targetable pathways to enhance HSC mobilization, we studied the role of hypoxia-inducible factor-1α (HIF-1α) and the effect of HIF-1α pharmacological stabilization on HSC mobilization in mice. We demonstrate in mice with HSC-specific conditional deletion of the Hif1a gene that the oxygen-labile transcription factor HIF-1α is essential for HSC mobilization in response to G-CSF and Plerixafor. Conversely, pharmacological stabilization of HIF-1α with the 4-prolyl hydroxylase inhibitor FG-4497 synergizes with G-CSF and Plerixafor increasing mobilization of reconstituting HSCs 20-fold compared with G-CSF plus Plerixafor, currently the most potent mobilizing combination used in the clinic.
Keywords
Date
2015
Type
Journal article
Journal
Leukemia
Book
Volume
29
Issue
6
Page Range
1366-1378
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Faculty of Health Sciences
Collections
Relation URI
Source URL
Event URL
Open Access Status
Open access
License
CC BY-NC 4.0
File Access
Open