Two forms of inherited deficiency of neutrophil numbers are cyclic hematopoiesis 
and severe congenital neutropenia. In cyclic hematopoiesis, neutrophil counts 
oscillate opposite monocytes in a 3-week cycle. Severe congenital neutropenia 
consists of static neutropenia and a predisposition to myelodysplasia and acute 
myelogenous leukemia. All cases of cyclic neutropenia and most cases of severe 
congenital neutropenia result from heterozygous germline mutations in the gene 
encoding neutrophil elastase, ela2. Recent work extends the list of neutropenia 
genes to include WASp, Gfi-1, adaptin, and tafazzin. Studies of mosaic patients 
suggest that ela2 mutations act in a cell-autonomous fashion. A hypothetical 
feedback circuit potentially interconnects these genes. Genetic dissection of 
signaling in model organisms along with experimental hematology implicate 
C/EPBepsilon, RUNX1/AML1, Notch family members, LEF1, and Cdc42 as additional 
nodes in this pathway. The authors propose that neutrophil elastase acts as an 
inhibitor of myelopoiesis, substantiating a chalone hypothesis proposed many 
years ago.