MOLECULAR GENETIC BASIS OF CYCLIC HEMATOPOIESIS

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Human cyclic hematopoiesis (also known as cyclic neutropenia, MIM #162800) is an autosomal dominant disease in which circulating blood cell counts oscillate with an invariant 21 day period resulting from periodic fluctuations in the production of cells by the bone marrow. The cycling of blood counts is most pronounced for neutrophils, causing opportunistic infections to arise during the neutropenic nadir, and monocytes, which cycle in a phase opposite to that of neutrophils. In preliminary studies genetic linkage analysis has been used to map the locus for cyclic hematopoiesis to chromosome 19p13.3 (maximum 2-point LOD score of 13.1 at theta = 0) and with a positional cloning strategy 7 different single base substitutions have been identified in the gene encoding neutrophil elastase, a chymotryptic serine protease of neutrophil and monocyte granules, in 13 of 13 families as well as a new mutation in one sporadic case. Neutrophil elastase is the target for protease inhibition by alpha-1-antitrypsin, and its unopposed release is involved in tissue damage at sites of inflammation. The mutations responsible for cyclic hematopoiesis cluster in regions of the molecule implicated in substrate specificity and interaction with alpha-1- antitrypsin. We hypothesize that a perturbed interaction between neutrophil elastase and its inhibitors or other biochemical abnormality may interrupt a feedback circuit and thereby lead to hematopoietic cycling. We propose Specific Aims to investigate the molecular genetic effects of the observed mutations and plan to link the biochemical deficit to the biological observation of hematopoietic cycling through a transgenic mouse model containing various human constructs crossed into genetic backgrounds which modify neutrophil elastase and alpha-1-antitrypsin interactions. The broad, long-term objective is to understand the 21 day biological clock of the bone marrow, whose cycle is made evident in this disease.