Published online
doi:10.1084/jem.20090693
The Journal of Experimental Medicine, Vol. 206, No. 8, 1701-1707
The Rockefeller University Press, 0022-1007 $30.00
© Plo et al.
An activating mutation in the CSF3R gene induces a hereditary chronic neutrophilia
Isabelle Plo1,2,3,
Yanyan Zhang1,2,3,
Jean-Pierre Le Couédic1,2,3,
Mayuka Nakatake1,2,3,
Jean-Michel Boulet4,
Miki Itaya5,
Steven O. Smith5,
Najet Debili1,2,3,
Stefan N. Constantinescu6,7,
William Vainchenker1,2,3,
Fawzia Louache1,2,3, and
Stéphane de Botton1,2,3,8
1 Research Laboratory on Hematopoiesis and Normal and Leukemic Stem Cells, U790, Institut National de la Santé et de la Recherche Médicale, 94805 Villejuif, France
2 Université Paris-Sud 11, 94805 Villejuif, France
3 Institut Gustave Roussy, Institut Fédératif de Recherche 34, 94805 Villejuif, France
4 Centre Hospitalier Régional Orléans, Hôpital de la Source, 45000 Orléans, France
5 Department of Biochemistry and Cell Biology, Center for Structural Biology, Stony Brook University, Stony Brook, NY 11794
6 Ludwig Institute for Cancer Research, 1200 Brussels, Belgium
7 de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium
8 Department of Hematology, Institut Gustave Roussy, 94805 Villejuif, France
CORRESPONDENCE William Vainchenker: verpre{at}igr.fr
We identify an autosomal mutation in the CSF3R gene in a family with a chronic neutrophilia. This T617N mutation energetically favors dimerization of the granulocyte colony-stimulating factor (G-CSF) receptor transmembrane domain, and thus, strongly promotes constitutive activation of the receptor and hypersensitivity to G-CSF for proliferation and differentiation, which ultimately leads to chronic neutrophilia. Mutant hematopoietic stem cells yield a myeloproliferative-like disorder in xenotransplantation and syngenic mouse bone marrow engraftment assays. The survey of 12 affected individuals during three generations indicates that only one patient had a myelodysplastic syndrome. Our data thus indicate that mutations in the CSF3R gene can be responsible for hereditary neutrophilia mimicking a myeloproliferative disorder.
I. Plo and Y. Zhang contributed equally to this paper.
Abbreviations used: G-CSF-R, G-CSF receptor; HSC, hematopoietic stem cell; MPD, myeloproliferative disorder; qRT-PCR, quantitative real-time PCR; SCF, stem cell factor; TM, transmembrane; TPO, thrombopoietin.
© 2009 Plo et al.
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