Koch Corinna, Samareh Bardia, Morishima Tatsuya, Mir Perihan, Kanz Lothar, Zeidler Cornelia, Skokowa Julia, Welte Karl
Department of Molecular Hematopoiesis, Hannover Medical School, Hannover, Germany.
Department of Hematology, Oncology, Immunology, Rheumatology and Pulmonology, University Hospital Tübingen, Tübingen, Germany.
Ann Hematol. 2017 Mar;96(3):345-353. doi: 10.1007/s00277-016-2894-5. Epub 2016 Dec 14.
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.
严重先天性中性粒细胞减少症（CN）是一种骨髓衰竭综合征，其特征为绝对中性粒细胞计数（ANC）低于500个细胞/μL，并伴有反复发生的、危及生命的细菌感染。大多数CN患者使用粒细胞集落刺激因子（G-CSF）治疗后ANC会升高。相反，粒细胞-巨噬细胞集落刺激因子（GM-CSF）在体外和体内均无法增加CN患者的中性粒细胞数量，这表明GM-CSF受体下游的信号通路存在特定缺陷。最近，我们检测到G-CSF通过髓系细胞中烟酰胺磷酸核糖转移酶（NAMPT）/沉默调节蛋白1信号的过度激活来诱导CN患者的粒细胞生成。在此，我们证明，与G-CSF不同，GM-CSF无法在CN患者中诱导NAMPT依赖的粒细胞生成。我们进一步确定NAMPT信号是髓系造血中GM-CSF通路的重要下游效应器。
