|
|
Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-05-1372.
 Previous Article | Table of Contents | Next Article 
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.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
D. S. Grenda, M. Murakami, J. Ghatak, J. Xia, L. A. Boxer, D. Dale, M. C. Dinauer, and D. C. Link
Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis
Blood,
December 15, 2007;
110(13):
4179 - 4187.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Duan, R. E. Person, H.-H. Lee, S. Huang, J. Donadieu, R. Badolato, H. L. Grimes, T. Papayannopoulou, and M. S. Horwitz
Epigenetic Regulation of Protein-Coding and MicroRNA Genes by the Gfi1-Interacting Tumor Suppressor PRDM5
Mol. Cell. Biol.,
October 1, 2007;
27(19):
6889 - 6902.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. S. Horwitz, Z. Duan, B. Korkmaz, H.-H. Lee, M. E. Mealiffe, and S. J. Salipante
Neutrophil elastase in cyclic and severe congenital neutropenia
Blood,
March 1, 2007;
109(5):
1817 - 1824.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Nasirikenari, B. H. Segal, J. R. Ostberg, A. Urbasic, and J. T. Lau
Altered granulopoietic profile and exaggerated acute neutrophilic inflammation in mice with targeted deficiency in the sialyltransferase ST6Gal I
Blood,
November 15, 2006;
108(10):
3397 - 3405.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Horwitz
Neutrophil elastase unleashed
Blood,
May 1, 2005;
105(9):
3392 - 3393.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Massullo, L. J. Druhan, B. A. Bunnell, M. G. Hunter, J. M. Robinson, C. B. Marsh, and B. R. Avalos
Aberrant subcellular targeting of the G185R neutrophil elastase mutant associated with severe congenital neutropenia induces premature apoptosis of differentiating promyelocytes
Blood,
May 1, 2005;
105(9):
3397 - 3404.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F.-Q. Li, R. E. Person, K.-I. Takemaru, K. Williams, K. Meade-White, A. H. Ozsahin, T. Gungor, R. T. Moon, and M. Horwitz
Lymphoid Enhancer Factor-1 Links Two Hereditary Leukemia Syndromes through Core-binding Factor {alpha} Regulation of ELA2
J. Biol. Chem.,
January 23, 2004;
279(4):
2873 - 2884.
[Abstract]
[Full Text]
[PDF]
|
|
|
| |
