HIF-1 alpha is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1 alpha
AuthorForristal, CE; Nowlan, B; Jacobsen, RN; Barbier, V; Walkinshaw, G; Walkley, CR; Winkler, IG; Levesque, JP
PublisherNATURE PUBLISHING GROUP
University of Melbourne Author/sWalkley, Carl
AffiliationMedicine and Radiology
Document TypeJournal Article
CitationsForristal, C. E., Nowlan, B., Jacobsen, R. N., Barbier, V., Walkinshaw, G., Walkley, C. R., Winkler, I. G. & Levesque, J. P. (2015). HIF-1 alpha is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1 alpha. LEUKEMIA, 29 (6), pp.1366-1378. https://doi.org/10.1038/leu.2015.8.
Access StatusOpen Access
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.
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