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Eltrombopag Promotes DNA Repair in Human Hematopoietic Stem and Progenitor Cells: Implications for the Treatment of Fanconi Anemia

Friday, September 15, 2017 — Poster Session IV

1:00 p.m. – 2:30 p.m.
FAES Terrace


  • KL Guenther
  • PS Cheruku
  • RH Smith
  • A Larochelle


Fanconi anemia (FA) is an inherited genomic instability syndrome resulting in a high incidence of bone marrow failure (BMF). Safe, curative options are currently unavailable. Recent studies have demonstrated that thrombopoietin (TPO) promotes DNA repair in hematopoietic stem/progenitor cells (HSPCs). However, recombinant TPO is no longer approved for clinical applications. Eltrombopag, a small molecule TPO receptor agonist, has been used to treat life-threatening cytopenias in patients with acquired BMF. In this study, we investigate whether culturing CD34+ HSPCs in the presence of eltrombopag or TPO prior to induction of double strand breaks (DSBs) by ¿-irradiation promotes DNA repair. Five hours after irradiation, HSPCs cultured with eltrombopag or TPO resolved most DSBs, while much higher percentages of cells with DSBs persisted in the control group. In colony forming unit (CFU) progenitor assays, ¿-irradiated HSPCs cultured with eltrombopag or TPO yielded 4- to 6-fold more CFUs than control SF groups, indicating increased HSPC survival in the presence of eltrombopag or TPO. To gain insight into the primary mechanism of DNA repair promoted by eltrombopag and TPO, we inhibited DNA-PK, an essential component of the classical NHEJ (C-NHEJ) pathway. Addition of a DNA-PK inhibitor (NU7441) completely abrogated the enhanced DSB repair observed with eltrombopag and TPO. Overall, our data indicate that epag and TPO enhance DSB repair in human HSPCs by promoting the fast-operating and faithful C-NHEJ pathway. A phase II clinical trial is in development to assess safety and efficacy of epag in the treatment of hematological manifestations of FA.

Category: Stem Cell Biology