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  LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia

Skokowa, J., Cario, G., Uenalan, M., Schambach, A., Germeshausen, M., Battmer, K., et al. (2006). LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia. Nature Medicine, 12, 1191-1197. doi:10.1038/nm1474.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0007-AC69-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0007-AC6A-1
Genre: Journal Article

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Skokowa 2006_ Nat Med.pdf (Publisher version), 338KB
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Skokowa 2006_ Nat Med.pdf
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https://www.nature.com/articles/nm1474 (Publisher version)
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 Creators:
Skokowa, Julia1, Author
Cario, Gunnar1, Author
Uenalan, Murat1, Author
Schambach, Axel1, Author
Germeshausen, Manuela1, Author
Battmer, Karin1, Author
Zeidler, Cornelia1, Author
Lehmann, Ulrich1, Author
Eder, Matthias1, Author
Baum, Christopher1, Author
Grosschedl, Rudolf2, Author              
Stanulla, Martin1, Author
Scherr, Michaela1, Author
Welte, Karl1, Author
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1External Organizations, ou_persistent22              
2Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243641              

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 Abstract: We demonstrate here that lymphoid enhancer-binding factor 1 (LEF-1) mediates the proliferation, survival and differentiation of granulocyte progenitor cells. We initially documented the importance of this transcription factor in the bone marrow of individuals with severe congenital neutropenia (CN) with a 'differentiation block' at the promyelocytic stage of myelopoiesis. LEF-1 expression was greatly reduced or even absent in CN arrested promyelocytes, resulting in defective expression of the LEF-1 target genes CCND1, MYC and BIRC5, encoding cyclin D1, c-Myc and survivin, respectively. In contrast, healthy individuals showed highest LEF-1 expression in promyelocytes. Reconstitution of LEF-1 in early hematopoietic progenitors of two individuals with CN corrected the defective myelopoiesis and resulted in the differentiation of these progenitors into mature granulocytes. Repression of endogenous LEF-1 by specific short hairpin RNA inhibited proliferation and induced apoptosis of CD34+ progenitors from healthy individuals and of cells from two myeloid lines (HL-60 and K562). C/EBPα, a key transcription factor in granulopoiesis, was directly regulated by LEF-1. These observations indicate that LEF-1 is an instructive factor regulating neutrophilic granulopoiesis whose absence plays a critical role in the defective maturation program of myeloid progenitors in individuals with CN. NOTE: In the version of this article initially published, the DOI was incorrect. The correct DOI is 10.1038/nm1474. The error has been corrected in the HTML and PDF versions of the article.

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Language(s): eng - English
 Dates: 2006-09-24
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1038/nm1474
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Title: Nature Medicine
  Other : Nat. Med.
Source Genre: Journal
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Publ. Info: New York, NY : Nature Pub. Co.
Pages: - Volume / Issue: 12 Sequence Number: - Start / End Page: 1191 - 1197 Identifier: ISSN: 1078-8956
CoNE: https://pure.mpg.de/cone/journals/resource/954925606824