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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-05-1372.
Submitted May 9, 2002
Accepted June 14, 2002
Mice expressing a neutrophil elastase mutation derived from patients with severe congenital neutropenia have normal granulopoiesis
David S Grenda, Sonja E Johnson, Jill R Mayer, Morgan L McLemore, Kathleen F Benson, Marshall Horwitz, and Daniel C Link*
Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
* Corresponding author; email: dlink{at}im.wustl.edu.
Severe congenital neutropenia (SCN) is a syndrome characterized by an isolated block in granulocytic differentiation and an increased risk of developing acute myeloid leukemia (AML). Recent studies have demonstrated that the majority of patients with SCN and cyclic neutropenia, a related disorder characterized by periodic oscillations in the number of circulating neutrophils, have heterozygous germline mutations in the ELA2 gene encoding neutrophil elastase (NE). To test the hypothesis that these mutations are causative for SCN, we generated transgenic mice carrying a targeted mutation of their Ela2 gene ("V72M") reproducing a mutation found in two unrelated patients with SCN, one of whom developed acute myeloid leukemia. Expression of mutant NE mRNA and enzymatically active protein was confirmed. Mice heterozygous and homozygous for the V72M allele have normal numbers of circulating neutrophils, and no accumulation of myeloid precursors in the bone marrow was observed. Serial blood analysis found no evidence of cycling in any of the major hematopoietic lineages. Rates of apoptosis following cytokine deprivation were similar in wild type and mutant neutrophils, as were the frequency and cytokine responsiveness of myeloid progenitors. The stress granulopoiesis response, as measured by neutrophil recovery after cyclophosphamide-induced myelosuppresion, was normal. To define the leukemogenic potential of V72M NE, a tumor watch was established. To date, no cases of leukemia have been detected. Collectively, these data suggest that expression of V72M NE is not sufficient to induce an SCN phenotype or leukemia in mice.
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