Granulocyte colony-stimulating factor and its receptor in normal myeloid cell development, leukemia and related blood cell disorders

Abstract

Granulocyte colony-stimulating factor (G-CSF) is the major hematopoietic cytokine involved in the control of neutrophil production and thus serves as a critical regulator of the innate immunity against bacterial infections. G-CSF is applied on a routine basis in the clinic for treatment of congenital and acquired neutropenias, diseases characterized by a critical shortage of neutrophils, leading to severe opportunistic bacterial infections. Very recently, it has become clear that therapeutic application of G-CSF may not be limited to different types of neutropenia, but may extend to non-hematological conditions, in particular cardiac and brain infarctions. G-CSF drives the proliferation, survival and neutrophilic differentiation of myeloid progenitor cells by activation of a receptor of the hematopoietin receptor superfamily, which subsequently triggers multiple signaling mechanisms. These mechanisms exert positive as well as negative effects on the signaling function of the G-CSF receptor. The integrated output of these signaling pathways provide the appropriate balance needed for accurate production of neutrophils under both steady state and "emergency" conditions. Here we review how these mechanisms are thought to act in concert to meet with these demands and how perturbations in the function of the G-CSF receptor are implicated in various types of myeloid disease.

The zebrafish granulocyte colony-stimulating factors (Gcsfs): 2 paralogous cytokines and their roles in hematopoietic development and maintenance

“…[1][2][3][4][5] Gcsf exerts these actions through binding to its cognate receptor, Gcsfr, activating downstream signaling cascades important for the survival, migration, proliferation, and differentiation of neutrophils during steady-state and emergency hematopoiesis. 6 Gcsf is predominantly produced by cells of the monocyte/mw lineage but is also produced by endothelial cells, 7 fibroblasts, 8 and mesothelial cells 9 under proper stimulatory conditions. Importantly, Gcsfr is present on a variety of hematopoietic cells, including myeloid progenitors, mature neutrophils, monocytes, B cells, and T cells.…”

Peroxiredoxin-controlled G-CSF signalling at the endoplasmic reticulum–early endosome interface

“…Granulocyte colony-stimulating factor (G-CSF) is the major hematopoietic growth factor involved in the production of neutrophils (Demetri and Griffin, 1991;Lieschke et al, 1994;Touw and van de Geijn, 2007). G-CSF induces the proliferation, survival and neutrophilic differentiation of myeloid progenitor cells, which are cellular responses that require a balanced activation and subsequent attenuation of signalling pathways linked to the G-CSFR (Touw and van de Geijn, 2007), a member of the cytokine receptor class I superfamily (Wells and de Vos, 1996).…”

“…G-CSF induces the proliferation, survival and neutrophilic differentiation of myeloid progenitor cells, which are cellular responses that require a balanced activation and subsequent attenuation of signalling pathways linked to the G-CSFR (Touw and van de Geijn, 2007), a member of the cytokine receptor class I superfamily (Wells and de Vos, 1996). Signal attenuation of the G-CSFR is severely compromised by mutations causing truncations in the cytoplasmic domain of the G-CSFR, as observed in severe congenital neutropenia (SCN) patients showing disease progression to acute myeloid leukaemia (AML) (Dong et al, 1995;Freedman and Alter, 2002;Germeshausen, 2007).…”

Prevalence of a new auto-activating colony stimulating factor 3 receptor mutation (CSF3R-T595I) in acute myeloid leukemia and severe congenital neutropenia

“…4 Acquisition of nonsense CSF3R mutations that truncate the carboxyl-terminus from the CSF3R protein is a common phenomenon in SCN patients. 5 Studies in a variety of in vitro and in vivo models have established that these truncated CSF3R proteins confer elevated CSF3-induced proliferative responses to myeloid progenitors.…”