Thrombopoietin-Increased DNA-PK-Dependent DNA Repair Limits Hematopoietic Stem and Progenitor Cell Mutagenesis in Response to DNA Damage
Menée in vitro et sur un modèle murin, cette étude montre que l'administration de thrombopoïétine augmente l'efficacité de la protéine kinase dépendante de l'ADN, une enzyme impliquée dans la réparation de l'ADN, et réduit ainsi le risque de mutagenèse des cellules souches hématopoïétiques et des cellules progénitrices après une radiothérapie
DNA double-strand breaks (DSBs) represent a serious threat for hematopoietic stem cells (HSCs). How cytokines and environmental signals integrate the DNA damage response and contribute to HSC-intrinsic DNA repair processes remains unknown. Thrombopoietin (TPO) and its receptor, Mpl, are critical factors supporting HSC self-renewal and expansion. Here, we uncover an unknown function for TPO-Mpl in the regulation of DNA damage response. We show that DNA repair following ³-irradiation (³-IR) or the action of topoisomerase-II inhibitors is defective in Mpl / and in wild-type mouse or human hematopoietic stem and progenitor cells treated in the absence of TPO. TPO stimulates DNA repair in vitro and in vivo by increasing DNA-PK-dependent nonhomologous end-joining efficiency. This ensures HSC chromosomal integrity and limits their long-term injury in response to IR. This shows that niche factors can modulate the HSC DSB repair machinery and opens new avenues for administration of TPO agonists for minimizing radiotherapy-induced HSC injury and mutagenesis. º Mpl loss increases ³-irradiation-induced genomic instability in HSPCs º TPO promotes DNA repair in vitro and in vivo in HSPCs º TPO increases DNA-PK activity and NHEJ-mediated repair efficiency in HSPCs º A single TPO injection before mouse TBI limits long-term HSC injury and mutagenesis Administration of Thrombopoietin before radiotherapy minimizes hematopoietic stem cell injury and mutagenesis in mice.
http://linkinghub.elsevier.com/retrieve/pii/S1934590912006352