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Blood, 15 October 2006, Vol. 108, No. 8, pp. 2562-2568.
Prepublished online as a Blood First Edition Paper on June 13, 2006; DOI 10.1182/blood-2006-05-024307.


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Submitted May 19, 2006
Accepted May 31, 2006

Src-family kinases are important negative regulators of G-CSF dependent granulopoiesis

Craig H Mermel, Morgan L McLemore, Fulu Liu, Shalini Pereira, Jill Woloszynek, Clifford A Lowell, and Daniel C Link*

Division of Oncology, Washington University, Missouri, USA
Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas
Department of Laboratory Medicine, University of California, San Francisco, CA, USA

* Corresponding author; email: dlink{at}im.wustl.edu.

Granulocyte colony stimulating factor (G-CSF) is the principal cytokine regulating granulopoiesis. Truncation mutations of the G-CSF receptor (G-CSFR) are associated with the development of acute myeloid leukemia in patients with severe congenital neutropenia. Though increased proliferative signaling by a representative G-CSFR truncation mutation (termed d715) has been documented, the molecular basis for this hyperproliferative phenotype has not been fully characterized. Given the accumulating evidence implicating Src-family kinases in the transduction of cytokine receptor signals, the role of these kinases in the regulation of G-CSF signaling was examined. We show that Hck and Lyn, Src-family kinases expressed in myeloid cells, are negative regulators of granulopoiesis that act at distinct stages of granulocytic differentiation. Whereas Hck regulates the G-CSF induced proliferation of granulocytic precursors, Lyn regulates the production of myeloid progenitors. Interestingly, d715 G-CSFR myeloid progenitors were resistant to the growth-stimulating effect of treatment with a Src kinase inhibitor. Together, these data establish Lyn and Hck as key negative regulators of granulopoiesis and raise the possibility that loss of Src-family kinase activation by the d715 G-CSFR may contribute to its hyperproliferative phenotype.


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