Highlights d LT-HSCs conserve epigenetic memory of previous infectious challenge d Increased transcriptional response of open myeloid enhancers to secondary stimulation d Memory improves myeloid differentiation and resistance to secondary infection

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.

The originally published version of this article contained a number of minor mistakes and typos that were accidentally introduced by the publisher during the production process, including an incorrect definition for GMP ("granulocyte-monocyte progenitors guanosine monophosphate" instead of the correct "granulocyte-monocyte progenitors"), and minor mistakes and typos that the publisher failed to correct, including changing "(D)" to "(E)" in the legend to Figure 4C and adding text to the legend to Figure 1 to clarify that the disease-free survival curves of mice described in (A) and (C) appear in (B) and (D), respectively. All such mistakes have now been corrected. The publisher apologizes for these errors and any resulting confusion.