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

Author
item SKOKOWA, JULIA - Hannover University
item LAN, DAN - Hannover University
item THAKUR, BASANT - Hannover University
item WANG, FEI - Children'S Nutrition Research Center (CNRC)
item GUPTA, KSHAMA - Hannover University
item CARIO, GUNNAR - University Of Kiel
item BRECHLIN, ANNETTE - Hannover University
item SCHAMBACK, AXEL - Hannover University
item HINRICHSEN, LARS - Hannover University
item MEYER, GUSTAV - Hannover University
item GAESTEL, MATTHIAS - Hannover University
item STANULLA, MARTIN - Hannover University
item TONG, QIANG - Children'S Nutrition Research Center (CNRC)
item WELTE, KARL - Hannover University

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.