Nasri Masoud, Dannenmann Benjamin, Doll Larissa, Findik Betül, Bernhard Franka, Kandabarau Sergey, Klimiankou Maksim, Gawaz Meinrad, Lengerke Claudia, Zeidler Cornelia, Welte Karl, Skokowa Julia
Department of Oncology, Hematology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, 72076 Tuebingen, Germany.
Department of Cardiology and Angiology, University Hospital Tuebingen, 72076 Tuebingen, Germany.
Mol Ther. 2025 Jun 4;33(6):2851-2871. doi: 10.1016/j.ymthe.2024.10.031. Epub 2024 Dec 8.
Severe congenital neutropenia (CN) patients require life-long treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF), but some show no response. We sought to establish a therapy for CN that targets signaling pathways causing maturation arrest of granulocytic progenitors. We developed an isogenic induced pluripotent stem cell (iPSC) in vitro model of CN associated with ELANE mutations (ELANE-CN) and performed an in silico drug repurposing analysis of the transcriptomics of iPSC-generated hematopoietic stem and progenitor cells. We identified flavopiridol, a Food and Drug Administration (FDA)-approved pan-cyclin-dependent kinase inhibitor, as a potential therapeutic. Treatment with low-dose flavopiridol rescued defective granulopoiesis in primary CD34 cells of CN patients with different inherited gene mutations in vitro and in two zebrafish CN models in vivo without any toxic effects and leading to functional granulocytes. Flavopiridol also restored granulopoiesis caused by diminished CEBPA expression, a known defective signaling molecule in CN. Thus, we described for the first time a potential therapy for CN with flavopiridol that could be potentially used to treat patients with different types of neutropenia.
严重先天性中性粒细胞减少症（CN）患者需要用重组人粒细胞集落刺激因子（rhG-CSF）进行终身治疗，但有些患者并无反应。我们试图建立一种针对导致粒细胞祖细胞成熟停滞的信号通路的CN治疗方法。我们构建了一种与ELANE突变相关的CN的同基因诱导多能干细胞（iPSC）体外模型（ELANE-CN），并对iPSC生成的造血干细胞和祖细胞的转录组进行了计算机药物再利用分析。我们确定了一种美国食品药品监督管理局（FDA）批准的泛细胞周期蛋白依赖性激酶抑制剂黄酮哌酯作为一种潜在的治疗药物。低剂量黄酮哌酯治疗可挽救体外培养的患有不同遗传基因突变的CN患者原代CD34细胞以及两种体内斑马鱼CN模型中存在缺陷的粒细胞生成，且无任何毒性作用，并产生功能性粒细胞。黄酮哌酯还恢复了由CEBPA表达减少引起的粒细胞生成，CEBPA是CN中一种已知的缺陷信号分子。因此，我们首次描述了黄酮哌酯对CN的潜在治疗作用，它可能被用于治疗不同类型中性粒细胞减少症的患者。
