Abstract

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.