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Article
Nature Medicine 15, 151 - 158 (2009)
Published online: 1 February 2009 | doi:10.1038/nm.1913
NAMPT is essential for the G-CSF–induced myeloid differentiation via a NAD+–sirtuin-1–dependent pathway
Julia Skokowa1,7, Dan Lan1,6,7, Basant Kumar Thakur1, Fei Wang2, Kshama Gupta1, Gunnar Cario3, Annette Müller Brechlin1, Axel Schambach4, Lars Hinrichsen1, Gustav Meyer5, Matthias Gaestel5, Martin Stanulla1,3, Qiang Tong2 & Karl Welte1
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.
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