NAMPT is essential for the G-CSF-induced myeloid differentiation via a NAD(+)-sirtuin-1-dependent pathway.
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.
Skokowa
Julia
J
Department of Molecular Hematopoiesis, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. skokowa.julia@mh-hannover.de
Lan
Dan
D
Thakur
Basant Kumar
BK
Wang
Fei
F
Gupta
Kshama
K
Cario
Gunnar
G
Brechlin
Annette Müller
AM
Schambach
Axel
A
Hinrichsen
Lars
L
Meyer
Gustav
G
Gaestel
Matthias
M
Stanulla
Martin
M
Tong
Qiang
Q
Welte
Karl
K
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*
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