Post-transplant G-CSF impedes engraftment of gene-edited human hematopoietic stem cells by exacerbating p53-mediated DNA damage response.

ABSTRACT: Granulocyte-colony-stimulating factor (G-CSF) is commonly used to accelerate recovery from neutropenia following chemotherapy and autologous transplantation of hematopoietic stem and progenitor cells (HSPCs) for malignant disorders. However, its utility after ex vivo gene therapy in human HSPCs remains unexplored. We show that administering G-CSF from day 1 to 14 post-transplant impedes engraftment of CRISPR-Cas9 gene-edited human HSPCs in murine xenograft models. G-CSF affects gene-edited HSPCs through a cell-intrinsic mechanism, causing proliferative stress and amplifying the early p53-mediated DNA damage response triggered by Cas9-mediated DNA double-strand breaks. This underscores a threshold mechanism where p53 activation must reach a critical level to impair cellular function. Transi

SUBMITTER: Araki D 

PROVIDER: S-EPMC11698648 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature