HIF-1α is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1α
Journal article
Forristal, C. E., Nowlan, B., Jacobsen, R. N., Barbier, V., Walkinshaw, G., Walkley, Carl, Winkler, I. G. and Levesque, J. P.. (2015). HIF-1α is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1α. Leukemia. 29(6), pp. 1366 - 1378. https://doi.org/10.1038/leu.2015.8
Authors | Forristal, C. E., Nowlan, B., Jacobsen, R. N., Barbier, V., Walkinshaw, G., Walkley, Carl, Winkler, I. G. and Levesque, J. P. |
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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. |
Year | 2015 |
Journal | Leukemia |
Journal citation | 29 (6), pp. 1366 - 1378 |
Publisher | Nature Publishing Group |
ISSN | 0887-6924 |
Digital Object Identifier (DOI) | https://doi.org/10.1038/leu.2015.8 |
Scopus EID | 2-s2.0-84930576484 |
Open access | Open access |
Page range | 1366 - 1378 |
Research Group | Mary MacKillop Institute for Health Research |
Publisher's version | License |
Place of publication | United Kingdom |
https://acuresearchbank.acu.edu.au/item/8q5yz/hif-1-is-required-for-hematopoietic-stem-cell-mobilization-and-4-prolyl-hydroxylase-inhibitors-enhance-mobilization-by-stabilizing-hif-1
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