title: Src family kinases are important negative regulators of G-CSF-dependent granulopoiesis.
abstract: 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. Although 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.
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8007, Saint Louis, MO 63110, USA.
authors.forename: Craig H
authors.initials: CH
authors.lastname: Mermel
authors.forename: Morgan L
authors.initials: ML
authors.lastname: McLemore
authors.forename: Fulu
authors.initials: F
authors.lastname: Liu
authors.forename: Shalini
authors.initials: S
authors.lastname: Pereira
authors.forename: Jill
authors.initials: J
authors.lastname: Woloszynek
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D038042:Myelopoiesis / Q000187:drug effects / Q000502:physiology*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics; D051572:Proto-Oncogene Proteins c-hck / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016179:Granulocyte Colony-Stimulating Factor; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck; C060902:lyn protein-tyrosine kinase; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases; D020929:Mitogen-Activated Protein Kinase Kinases