TY  - JOUR
AU  - Forristal, CE
AU  - Nowlan, B
AU  - Jacobsen, RN
AU  - Barbier, V
AU  - Walkinshaw, G
AU  - Walkley, CR
AU  - Winkler, IG
AU  - Levesque, JP
Y2  - 2021/02/03
Y1  - 2015/06/01
SN  - 0887-6924
UR  - http://hdl.handle.net/11343/258979
AB  - 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.
LA  - English
PB  - NATURE PUBLISHING GROUP
T1  - HIF-1 alpha is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1 alpha
DO  - 10.1038/leu.2015.8
IS  - Leukemia
VL  - 29
IS  - 6
SP  - 1366-1378
L1  - /bitstream/handle/11343/258979/PMC4498452.pdf?sequence=1&isAllowed=y
ER  -