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United States Department of Agriculture

Agricultural Research Service

Title: NAMPT is essential for the G-CSF-induced myeloid differentiation via a NAD+-sirtuin-1-dependent pathway

item Skokowa, Julia
item Lan, Dan
item Thakur, Basant
item Wang, Fei
item Gupta, Kshama
item Cario, Gunnar
item Brechlin, Annette
item Schamback, Axel
item Hinrichsen, Lars
item Meyer, Gustav
item Gaestel, Matthias
item Stanulla, Martin
item Tong, Qiang
item Welte, Karl

Submitted to: Nature Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/16/2008
Publication Date: 2/1/2009
Citation: Skokowa, J., Lan, D., Thakur, B.K., Wang, F., Gupta, K., Cario, G., Brechlin, A.M., Schamback, A., Hinrichsen, L., Meyer, G., Gaestel, M., Stanulla, M., Tong, Q., Welte, K. 2009. NAMPT is essential for the G-CSF-induced myeloid differentiation via a NAD+-sirtuin-1-dependent pathway. Nature Medicine. 15(2):151-158.

Interpretive Summary: Severe congenital neutropenia is a disorder with increased death of precursor cells that give rise to neutrophils, a type of white blood cells. It was a fatal disease of early childhood before the introduction of the hormone therapy with the granulocyte colony–stimulating factor (G-CSF) treatment. We studied how G-CSF affects neutrophils and found G-CSF function through inducing an enzyme, which converts vitamin B3 to a substance that activates a program of neutrophil production to increase the number of these cells. We found that humans taking high doses of vitamin B3 have more neutrophil cells. These findings provide a novel treatment by taking vitamin B3 supplements to treat congenital neutropenia and other diseases with low neutrophils.

Technical 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-' and CCAAT/enhancer binding protein-', 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.

Last Modified: 07/25/2017
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