title: NAMPT is essential for the G-CSF-induced myeloid differentiation via a NAD(+)-sirtuin-1-dependent pathway.
abstract: We identified nicotinamide phosphoribosyltransferase (NAMPT), also known as pre-B cell colony enhancing factor (PBEF), as an essential enzyme mediating granulocyte colony-stimulating factor (G-CSF)-triggered granulopoiesis in healthy individuals and in individuals with severe congenital neutropenia. Intracellular NAMPT and NAD(+) amounts in myeloid cells, as well as plasma NAMPT and NAD(+) levels, were increased by G-CSF treatment of both healthy volunteers and individuals with congenital neutropenia. NAMPT administered both extracellularly and intracellularly induced granulocytic differentiation of CD34(+) hematopoietic progenitor cells and of the promyelocytic leukemia cell line HL-60. Treatment of healthy individuals with high doses of vitamin B3 (nicotinamide), a substrate of NAMPT, induced neutrophilic granulocyte differentiation. The molecular events triggered by NAMPT include NAD(+)-dependent sirtuin-1 activation, subsequent induction of CCAAT/enhancer binding protein-alpha and CCAAT/enhancer binding protein-beta, and, ultimately, upregulation of G-CSF synthesis and G-CSF receptor expression. G-CSF, in turn, further increases NAMPT levels. These results reveal a decisive role of the NAD(+) metabolic pathway in G-CSF-triggered myelopoiesis.
authors.affiliation: Department of Molecular Hematopoiesis, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. skokowa.julia@mh-hannover.de
authors.forename: Julia
authors.initials: J
authors.lastname: Skokowa
authors.forename: Dan
authors.initials: D
authors.lastname: Lan
authors.forename: Basant Kumar
authors.initials: BK
authors.lastname: Thakur
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.forename: Kshama
authors.initials: K
authors.lastname: Gupta
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cario
authors.forename: Annette Müller
authors.initials: AM
authors.lastname: Brechlin
authors.forename: Axel
authors.initials: A
authors.lastname: Schambach
authors.forename: Lars
authors.initials: L
authors.lastname: Hinrichsen
authors.forename: Gustav
authors.initials: G
authors.lastname: Meyer
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.forename: Qiang
authors.initials: Q
authors.lastname: Tong
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
mesh_terms: D002454:Cell Differentiation / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology*; D006098:Granulocytes / Q000166:cytology; D018922:HL-60 Cells; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D009243:NAD / Q000502:physiology*; D009536:Niacinamide / Q000494:pharmacology; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000502:physiology; D056564:Sirtuin 1; D037761:Sirtuins / Q000502:physiology*
chemical_list: D016207:Cytokines; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D009243:NAD; D016179:Granulocyte Colony-Stimulating Factor; D009536:Niacinamide; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins