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Neutrophil elastase is severely down-regulated in severe congenital neutropenia independent of ELA2 or HAX1 mutations but dependent on LEF-1.
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- Author(s): Skokowa J;Skokowa J; Fobiwe JP; Dan L; Thakur BK; Welte K
- Source:
Blood [Blood] 2009 Oct 01; Vol. 114 (14), pp. 3044-51. Date of Electronic Publication: 2009 Jul 20.
- Publication Type:
Journal Article; Research Support, Non-U.S. Gov't
- Language:
English
- Additional Information
- Source:
Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE
- Publication Information:
Publication: 2021- : [New York] : Elsevier
Original Publication: New York, Grune & Stratton [etc.]
- Subject Terms:
- Abstract:
Severe congenital neutropenia (CN) is a heterogeneous disorder of myelopoiesis which follows an autosomal dominant or autosomal recessive pattern of inheritance. Genetic analyses indicate mutations in the ELA2 gene in most patients. We have identified LEF-1 as a decisive transcription factor in granulopoiesis controlling proliferation and granulocytic differentiation by direct activation of its target gene, C/EBPalpha. In patients with CN, the expression of LEF-1 and C/EBPalpha was abrogated in myeloid progenitors leading to maturation arrest of granulopoiesis. In the present study we demonstrated that ELA2 mRNA expression in myeloid progenitors and plasma protein levels of neutrophil elastase (NE) were markedly reduced in patients with CN harboring mutations in either ELA2 or HAX-1 genes. The ELA2 gene promoter is positively regulated by the direct binding of LEF-1 or C/EBPalpha, documenting the role of LEF1 in the diminished ELA2 expression. We found that transduction of hematopoietic cells with LEF-1 cDNA resulted in the up-regulation of ELA2/NE synthesis, whereas inhibition of LEF-1 by shRNA led to a marked reduction in the levels of ELA2/NE. LEF-1 rescue of CD34(+) cells isolated from 2 patients with CN resulted in granulocytic differentiation of the cells which was in line with increased levels of functionally active ELA2/NE.
- Accession Number:
0 (Adaptor Proteins, Signal Transducing)
0 (CXCR4 protein, human)
0 (HAX1 protein, human)
0 (Lymphoid Enhancer-Binding Factor 1)
0 (Proteins)
0 (RNA, Messenger)
0 (Receptors, CXCR4)
143011-72-7 (Granulocyte Colony-Stimulating Factor)
EC 3.4.21.- (Serine Endopeptidases)
EC 3.4.21.37 (Leukocyte Elastase)
EC 3.4.21.71 (pancreatic elastase II)
- Publication Date:
Date Created: 20090722 Date Completed: 20091202 Latest Revision: 20210206
- Publication Date:
20240829
- Accession Number:
10.1182/blood-2008-11-188755
- Accession Number:
19620402
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