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  Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis

Skokowa, J., Klimiankou, M., Klimenkova, O., Lan, D., Gupta, K., Hussein, K., et al. (2012). Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis. Nature Medicine, 18, 1550-1559. doi:10.1038/nm.2958.

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Skokowa, Julia1, Author
Klimiankou, Maxim1, Author
Klimenkova, Olga1, Author
Lan, Dan1, Author
Gupta, Kshama1, Author
Hussein, Kais1, Author
Carrizosa, Esteban1, Author
Kusnetsova, Inna1, Author
Li, Zhixiong1, Author
Sustmann, Claudio2, Author              
Ganser, Arnold1, Author
Zeidler, Cornelia1, Author
Kreipe, Hans-Heinrich1, Author
Burkhardt, Janis1, Author
Grosschedl, Rudolf2, Author              
Welte, Karl1, Author
Affiliations:
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 found that hematopoietic cell-specific Lyn substrate 1 (HCLS1 or HS1) is highly expressed in human myeloid cells and that stimulation with granulocyte colony-stimulating factor (G-CSF) leads to HCLS1 phosphorylation. HCLS1 binds the transcription factor lymphoid-enhancer binding factor 1 (LEF-1), transporting LEF-1 into the nucleus upon G-CSF stimulation and inducing LEF-1 autoregulation. In patients with severe congenital neutropenia, inherited mutations in the gene encoding HCLS1-associated protein X-1 (HAX1) lead to profound defects in G-CSF-triggered phosphorylation of HCLS1 and subsequently to reduced autoregulation and expression of LEF-1. Consistent with these results, HCLS1-deficient mice are neutropenic. In bone marrow biopsies of the majority of tested patients with acute myeloid leukemia, HCLS1 protein expression is substantially elevated, associated with high levels of G-CSF synthesis and, in some individuals, a four-residue insertion in a proline-rich region of HCLS1 protein known to accelerate intracellular signaling. These data demonstrate the importance of HCLS1 in myelopoiesis in vitro and in vivo.

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Language(s): eng - English
 Dates: 2012-10
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1038/nm.2958
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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: 18 Sequence Number: - Start / End Page: 1550 - 1559 Identifier: ISSN: 1078-8956
CoNE: https://pure.mpg.de/cone/journals/resource/954925606824