title: HIF-1α is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1α.
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.
authors.affiliation: Blood and Bone Diseases Program, Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia.
authors.forename: C E
authors.initials: CE
authors.lastname: Forristal
authors.affiliation: Blood and Bone Diseases Program, Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Nowlan
authors.affiliation: 1] Blood and Bone Diseases Program, Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia [2] School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: R N
authors.initials: RN
authors.lastname: Jacobsen
authors.affiliation: Blood and Bone Diseases Program, Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia.
authors.forename: V
authors.initials: V
authors.lastname: Barbier
authors.affiliation: Fibrogen Inc., San Francisco, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Walkinshaw
authors.affiliation: Stem Cell Regulation Unit, St Vincent's Institute and University of Melbourne, St Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: C R
authors.initials: CR
authors.lastname: Walkley
authors.affiliation: Blood and Bone Diseases Program, Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia.
authors.forename: I G
authors.initials: IG
authors.lastname: Winkler
authors.affiliation: 1] Blood and Bone Diseases Program, Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia [2] School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: J P
authors.initials: JP
authors.lastname: Levesque
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D001596:Benzylamines; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000080027:Cyclams; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064828:Prolyl Hydroxylases / Q000502:physiology*; D064800:Prolyl-Hydroxylase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014182:Transplantation, Autologous
chemical_list: D019380:Anti-HIV Agents; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064800:Prolyl-Hydroxylase Inhibitors; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D016179:Granulocyte Colony-Stimulating Factor; D064828:Prolyl Hydroxylases; C088327:plerixafor