title: Multiple pathways contribute to the hyperproliferative responses from truncated granulocyte colony-stimulating factor receptors.
abstract: Mutations in the granulocyte colony-stimulating factor receptor (G-CSF-R) gene leading to a truncated protein have been identified in a cohort of neutropenia patients highly predisposed to acute myeloid leukemia. Such mutations act in a dominant manner resulting in hyperproliferation but impaired differentiation in response to G-CSF. This is due, at least in part, to defective internalization and loss of binding sites for several negative regulators, leading to sustained receptor activation. However, those signaling pathways responsible for mediating the hyperproliferative function have remained unclear. In this study, analysis of an additional G-CSF-R mutant confirmed the importance of residues downstream of Box 2 as important contributors to the sustained proliferation. However, maximal proliferation correlated with the ability to robustly activate signal transducer and activator of transcription (STAT) 5 in a sustained manner, whereas co-expression of dominant-negative STAT5, but not dominant-negative STAT3, was able to inhibit G-CSF-stimulated proliferation from a truncated receptor. Furthermore, a Janus kinase (JAK) inhibitor also strongly reduced the proliferative response, whereas inhibitors of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) or phosphatidylinositol (PI) 3-kinase reduced proliferation to a lesser degree. These data suggest that sustained JAK2/STAT5 activation is a major contributor to the hyperproliferative function of truncated G-CSF receptors, with pathways involving MEK and PI 3-kinase playing a reduced role.
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Gits
authors.forename: D
authors.initials: D
authors.lastname: van Leeuwen
authors.forename: H P
authors.initials: HP
authors.lastname: Carroll
authors.forename: I P
authors.initials: IP
authors.lastname: Touw
authors.forename: A C
authors.initials: AC
authors.lastname: Ward
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D053614:Janus Kinase 2 / Q000502:physiology; D020935:MAP Kinase Signaling System; D051379:Mice; D009154:Mutation; D015689:Oncogene Protein p21(ras) / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016188:Receptors, Granulocyte Colony-Stimulating Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D015689:Oncogene Protein p21(ras)