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.
