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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-05-1372.
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Blood, 1 November 2002, Vol. 100, No. 9, pp. 3221-3228
HEMATOPOIESIS
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
From the Division of Oncology, Department of Medicine,
Washington University School of Medicine, St Louis, MO, and Division of
Medical Genetics, Department of Medicine, University of Washington
School of Medicine, Seattle.
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 2 unrelated patients with SCN, one of whom developed AML. 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 myelosuppression,
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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