Thrombopoietin-increased DNA-PK-dependent DNA repair limits hematopoietic stem and progenitor cell mutagenesis in response to DNA damage

Cell Stem Cell. 2013 Jan 3;12(1):37-48. doi: 10.1016/j.stem.2012.10.012. Epub 2012 Dec 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle
  • Comet Assay
  • DNA Damage / genetics
  • DNA Damage / physiology*
  • Female
  • Fluorescent Antibody Technique
  • Hematopoietic Stem Cells / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mutagenesis / genetics
  • Mutagenesis / physiology*
  • Stem Cells / metabolism*
  • Thrombopoietin / genetics
  • Thrombopoietin / metabolism*


  • Thrombopoietin