Role of neutrophil elastase in bone marrow failure syndromes: molecular genetic revival of the chalone hypothesis

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. (C) 2003 Lippincott Williams Wilkins, Inc.