Research ArticleBlood Disorders

Thrombopoietin receptor–independent stimulation of hematopoietic stem cells by eltrombopag

See allHide authors and affiliations

Science Translational Medicine  12 Sep 2018:
Vol. 10, Issue 458, eaas9563
DOI: 10.1126/scitranslmed.aas9563

Ironing out bone marrow failure

Chronic thrombocytopenia can be associated with a variety of conditions, such as bone narrow failure syndromes and immune disorders. It increases the risk of severe bleeding, and therapies such as platelet transfusion or recombinant thrombopoietin are associated with a variety of complications. In contrast, the small-molecule eltrombopag, a thrombopoietin receptor agonist, has been very effective in treating thrombocytopenia in patients with bone marrow failure. Kao et al. demonstrated that, in addition to targeting the thrombopoietin receptor, eltrombopag also chelates iron and that this chelating action enables it to improve the function of bone marrow stem cells. The authors also determined the mechanism linking iron chelation to hematopoietic stem cell maintenance, which may help facilitate the development of future treatments.


Eltrombopag (EP), a small-molecule thrombopoietin receptor (TPO-R) agonist and potent intracellular iron chelator, has shown remarkable efficacy in stimulating sustained multilineage hematopoiesis in patients with bone marrow failure syndromes, suggesting an effect at the most immature hematopoietic stem and multipotent progenitor level. Although the functional and molecular effects of EP on megakaryopoiesis have been studied in the past, mechanistic insights into its effects on the earliest stages of hematopoiesis have been limited. We investigated the effects of EP treatment on hematopoietic stem cell (HSC) function using purified primary HSCs in separation-of-function mouse models, including a TPO-R–deficient strain, and stem cells isolated from patients undergoing TPO-R agonist treatment. Our mechanistic studies showed a stimulatory effect on stem cell self-renewal independently of TPO-R. Human and mouse HSCs responded to acute EP treatment with metabolic and gene expression alterations consistent with a reduction of intracellular labile iron pools that are essential for stem cell maintenance. Iron preloading prevented the stem cell stimulatory effects of EP. Moreover, comparative analysis of stem cells in the bone marrow of patients receiving EP showed a marked increase in the number of functional stem cells compared to patients undergoing therapy with romiplostim, another TPO-R agonist lacking an iron-chelating ability. Together, our study demonstrates that EP stimulates hematopoiesis at the stem cell level through iron chelation–mediated molecular reprogramming and indicates that labile iron pool–regulated pathways can modulate HSC function.

View Full Text

Stay Connected to Science Translational Medicine