title: Evidence that growth factor independence 1b regulates dormancy and peripheral blood mobilization of hematopoietic stem cells.
abstract: Donor-matched transplantation of hematopoietic stem cells (HSCs) is widely used to treat hematologic malignancies but is associated with high mortality. The expansion of HSC numbers and their mobilization into the bloodstream could significantly improve therapy. We report here that adult mice conditionally deficient for the transcription Growth factor independence 1b (Gfi1b) show a significant expansion of functional HSCs in the bone marrow and blood. Despite this expansion, Gfi1b(ko/ko) HSCs retain their ability to self-renew and to initiate multilineage differentiation but are no longer quiescent and contain elevated levels of reactive oxygen species. Treatment of Gfi1b(ko/ko) mice with N-acetyl-cystein significantly reduced HSC numbers indicating that increased reactive oxygen species levels are at least partially responsible for the expansion of Gfi1b-deficient HSCs. Moreover, Gfi1b(-/-) HSCs show decreased expression of CXCR4 and Vascular cell adhesion protein-1, which are required to retain dormant HSCs in the endosteal niche, suggesting that Gfi1b regulates HSC dormancy and pool size without affecting their function. Finally, the additional deletion of the related Gfi1 gene in Gfi1b(ko/ko) HSCs is incompatible with the maintenance of HSCs, suggesting that Gfi1b and Gfi1 have partially overlapping functions but that at least one Gfi gene is essential for the generation of HSCs.
authors.affiliation: Institut de recherches cliniques de Montréal, Canada.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Khandanpour
authors.forename: Ehssan
authors.initials: E
authors.lastname: Sharif-Askari
authors.forename: Lothar
authors.initials: L
authors.lastname: Vassen
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gaudreau
authors.forename: Jinfang
authors.initials: J
authors.lastname: Zhu
authors.forename: William E
authors.initials: WE
authors.lastname: Paul
authors.forename: Taro
authors.initials: T
authors.lastname: Okayama
authors.forename: Christian
authors.initials: C
authors.lastname: Kosan
authors.forename: Tarik
authors.initials: T
authors.lastname: Möröy
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D006631:Amine Oxidase (Copper-Containing) / Q000096:biosynthesis; D000818:Animals; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006706:Homeostasis; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000502:physiology*; D017382:Reactive Oxygen Species; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D012097:Repressor Proteins / Q000172:deficiency / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
chemical_list: C514936:CXCR4 protein, mouse; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; C486395:Gfi1b protein, mouse; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D019718:Receptors, CXCR4; D012097:Repressor Proteins; D014157:Transcription Factors; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse; D000111:Acetylcysteine
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