Gcsf Gcsfr and Neutrophil Elastase in Severe Chronic Neutropenia

Although G-CSF-deficient mice have life-long neutropenia, congenital or acquired neutropenia in humans caused by G-CSF deficiency itself has not been described. Approximately 20% of patients with severe chronic neutropenia have associated car-boxyl truncations of the G-CSF receptor (G-CSFR) (149,150), although these appear to be acquired somatic mutations rather than germline mutations (150). Representative examples of this mutation have been modeled in mice by targeted gene modification. In one model, based on a G-CSFR truncated at position 715, mice displayed baseline neu-tropenia, a milder haploinsufficiency phenotype, and a hyperproliferative response to exogenous G-CSF resulting in neutrophilia (151,152). In the other model, both heterozygous and homozygous mice displayed a normal basal granulopoietic phenotype with only a modest reduction in circulating neutrophil numbers, despite the lesion resulting in a hyperproliferative response to exogenous G-CSF in vivo (153). The reason for the difference between the two models is not clear, although the gene-targeting strategy used retained the selectable marker in one model (153) but not the other (151).

Recently, the genetic lesion resulting in cyclical neutropenia was located to the neu-trophil elastase gene (154). A high prevalence of heterozygous neutrophil elastase mutations in severe congenital neutropenia implicates these lesions epidemiologically in the pathogenesis of the disease (155). Normal granulopoiesis was observed in a murine model of one of these mutations (156), suggesting that the pathogenesis of the neutropenia may be more complex than the effects of a single mutation.

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