title: GM-CSF treatment is not effective in congenital neutropenia patients due to its inability to activate NAMPT signaling.
abstract: Severe congenital neutropenia (CN) is a bone marrow failure syndrome characterized by an absolute neutrophil count (ANC) below 500 cells/μL and recurrent, life-threatening bacterial infections. Treatment with granulocyte colony-stimulating factor (G-CSF) increases the ANC in the majority of CN patients. In contrary, granulocyte-monocyte colony-stimulating factor (GM-CSF) fails to increase neutrophil numbers in CN patients in vitro and in vivo, suggesting specific defects in signaling pathways downstream of GM-CSF receptor. Recently, we detected that G-CSF induces granulopoiesis in CN patients by hyperactivation of nicotinamide phosphoribosyl transferase (NAMPT)/Sirtuin 1 signaling in myeloid cells. Here, we demonstrated that, in contrast to G-CSF, GM-CSF failed to induce NAMPT-dependent granulopoiesis in CN patients. We further identified NAMPT signaling as an essential downstream effector of the GM-CSF pathway in myelopoiesis.
authors.affiliation: Department of Molecular Hematopoiesis, Hannover Medical School, Hannover, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Koch
authors.affiliation: Department of Hematology, Oncology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Bardia
authors.initials: B
authors.lastname: Samareh
authors.affiliation: Department of Hematology, Oncology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Morishima
authors.affiliation: Department of Hematology, Oncology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Perihan
authors.initials: P
authors.lastname: Mir
authors.affiliation: Department of Hematology, Oncology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Kanz
authors.affiliation: Department of Molecular Hematopoiesis, Hannover Medical School, Hannover, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zeidler
authors.affiliation: Department of Hematology, Oncology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Skokowa
authors.affiliation: Department of Hematology, Oncology and Bone Marrow Transplantation, Children's Hospital, University Hospital Tübingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany. Karl.Welte@med.uni-tuebingen.de.
authors.forename: Karl
authors.identifier: http://orcid.org/0000-0001-5178-3074
authors.initials: K
authors.lastname: Welte
mesh_terms: D002478:Cells, Cultured; D000080984:Congenital Bone Marrow Failure Syndromes; D016207:Cytokines / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism; D009503:Neutropenia / Q000151:congenital* / Q000188:drug therapy / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human
keywords: G-CSF; GM-CSF; NAMPT; Severe congenital neutropenia