title: Mice expressing a neutrophil elastase mutation derived from patients with severe congenital neutropenia have normal granulopoiesis.
abstract: 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.
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO 63110, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Grenda
authors.forename: Sonja E
authors.initials: SE
authors.lastname: Johnson
authors.forename: Jill R
authors.initials: JR
authors.lastname: Mayer
authors.forename: Morgan L
authors.initials: ML
authors.lastname: McLemore
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Benson
authors.forename: Marshall
authors.initials: M
authors.lastname: Horwitz
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
mesh_terms: D000208:Acute Disease; D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000503:physiopathology; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003433:Crosses, Genetic; D003520:Cyclophosphamide / Q000633:toxicity; D005260:Female; D018390:Gene Targeting; D005838:Genotype; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics; D007958:Leukocyte Count; D019272:Leukocyte Elastase / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D038042:Myelopoiesis / Q000235:genetics*; D009503:Neutropenia / Q000151:congenital / Q000235:genetics*; D009504:Neutrophils / Q000201:enzymology; D017354:Point Mutation; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics; D017384:Sequence Deletion; D013045:Species Specificity; D013047:Specific Pathogen-Free Organisms
chemical_list: D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide; D019272:Leukocyte Elastase