Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen.
Hematology and Oncology, Ordensklinikum Elisabethinen, Linz, Austria.
Haematologica. 2024 May 1;109(5):1393-1402. doi: 10.3324/haematol.2023.284033.
Mutations in the ELANE gene, encoding the neutrophil elastase (NE) protein, are responsible for most cyclic neutropenia (CyN) cases and approximately 25% of congenital neutropenia (CN) cases. In CN and in CyN, a median of 2.8% of CD34+ cells were early CD49f+ hematopoietic stem cells (eHSC) that did not express ELANE and thus escape from the unfolded protein response (UPR) caused by mutated NE. In CyN, the CD49f+ cells respond to granulocyte colony-stimulating factor (G-CSF) with a significant upregulation of the hematopoietic stem cell-specific transcription factors, C/EBPα, MLL1, HOXA9, MEIS1, and HLF during the ascending arm of the cycle, resulting in the differentiation of myeloid cells to mature neutrophils at the cycle peak. However, NE protein released by neutrophils at the cycle's peak caused a negative feedback loop on granulopoiesis through the proteolytic digestion of G-CSF. In contrast, in CN patients, CD49f+ cells failed to express mRNA levels of HSC-specific transcription factors mentioned above. Rescue of C/EBPα expression in CN restored granulopoiesis.
ELANE 基因（编码中性粒细胞弹性蛋白酶（NE）蛋白）的突变导致大多数周期性中性粒细胞减少症（CyN）病例和大约 25%的先天性中性粒细胞减少症（CN）病例。在 CN 和 CyN 中，中位数为 2.8%的 CD34+细胞是早期 CD49f+造血干细胞（eHSC），它们不表达 ELANE，因此逃避了由突变的 NE 引起的未折叠蛋白反应（UPR）。在 CyN 中，CD49f+细胞在循环的上升臂中对粒细胞集落刺激因子（G-CSF）做出反应，造血干细胞特异性转录因子 C/EBPα、MLL1、HOXA9、MEIS1 和 HLF 的表达显著上调，导致髓样细胞分化为成熟的中性粒细胞在循环高峰。然而，中性粒细胞在循环高峰释放的 NE 蛋白通过对 G-CSF 的蛋白水解消化对粒细胞生成产生负反馈环。相比之下，CN 患者的 CD49f+细胞未能表达上述 HSC 特异性转录因子的 mRNA 水平。在 CN 中恢复 C/EBPα 表达可挽救粒细胞生成。
Zotero 插件
