title: Thrombopoietin-increased DNA-PK-dependent DNA repair limits hematopoietic stem and progenitor cell mutagenesis in response to DNA damage.
abstract: 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 γ-irradiation (γ-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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France.
authors.forename: Bérengère
authors.initials: B
authors.lastname: de Laval
authors.forename: Patrycja
authors.initials: P
authors.lastname: Pawlikowska
authors.forename: Laurence
authors.initials: L
authors.lastname: Petit-Cocault
authors.forename: Chrystèle
authors.initials: C
authors.lastname: Bilhou-Nabera
authors.forename: Geneviève
authors.initials: G
authors.lastname: Aubin-Houzelstein
authors.forename: Michèle
authors.initials: M
authors.lastname: Souyri
authors.forename: Frédéric
authors.initials: F
authors.lastname: Pouzoulet
authors.forename: Murielle
authors.initials: M
authors.lastname: Gaudry
authors.forename: Françoise
authors.initials: F
authors.lastname: Porteu
mesh_terms: D000818:Animals; D002453:Cell Cycle; D020552:Comet Assay; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016296:Mutagenesis / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism*; D013926:Thrombopoietin / Q000235:genetics / Q000378:metabolism*
chemical_list: D013926:Thrombopoietin