Severe congenital neutropenia (CN) is a heterogeneous hematopoietic syndrome 
with a typical "maturation arrest" of granulocytic precursors at the 
promyelocytic stage, inherited in an autosomal dominant or recessive manner. 
Intriguingly, CN patients have the same bone marrow and blood phenotypes 
irrespective of inheritance. This suggests that mutations in various genes may 
lead to the dysregulation of the common myeloid transcription factor(s) in CN. 
To the extensively studied myeloid-specific transcription factors belong 
CCAAT/enhancer-binding proteins (C/EBPs) (-alpha, -beta, -epsilon) and PU.1. The 
relative levels of PU.1 and C/EBPalpha in granulocytic-macrophage progenitors 
have been suggested to regulate monocyte versus neutrophil cell-fate choice. In 
CN patients, the myelopoietic maturation program is sharply shifted toward 
monocytopoiesis, with increased levels of monocytes and no granulocytes in the 
peripheral blood. We found that in myeloid cells from CN patients C/EBPalpha and 
its target gene inhibitor of DNA binding 1 (Id1) are abrogated due to a lack of 
lymphoid enhancer-binding factor 1 (LEF-1) expression but PU.1 is slightly 
upregulated. Based on these findings, we conclude that in LEF-1-deficient 
myeloid cells from CN patients misbalanced C/EBPalpha/Id1:PU.1 ratio with a 
strong shift toward PU.1 could play a decisive role in the improper regulation 
of myelopoiesis with defective granulocytopoiesis and elevated monocytic 
differentiation. Recently, 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 
CN. Since CN patients respond to G-CSF treatment even in the absence of LEF-1 
and C/EBPalpha, we conclude that treatment of CN patients with pharmacological 
doses of G-CSF activates NAMPT/NAD(+)/SIRT1-dependent "emergency" granulopoiesis 
via C/EBPbeta.