Thrombopoietin receptor-independent stimulation of hematopoietic stem cells by eltrombopag

Yun Ruei Kao, Jiahao Chen, Swathi-Rao Narayanagari, Tihomira I. Todorova, Maria M. Aivalioti, Mariana Ferreira, Pedro M. Ramos, Celine Pallaud, Ioannis Mantzaris, Aditi Shastri, James B. Bussel, Amit K. Verma, Ulrich G. Steidl, Britta Will

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbereaas9563
JournalScience Translational Medicine
Volume10
Issue number458
DOIs
StatePublished - Sep 12 2018

Fingerprint

Thrombopoietin Receptors
Hematopoietic Stem Cells
Stem Cells
Iron
Hematopoiesis
Therapeutics
Chelating Agents
eltrombopag
Bone Marrow
Maintenance
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Thrombopoietin receptor-independent stimulation of hematopoietic stem cells by eltrombopag. / Kao, Yun Ruei; Chen, Jiahao; Narayanagari, Swathi-Rao; Todorova, Tihomira I.; Aivalioti, Maria M.; Ferreira, Mariana; Ramos, Pedro M.; Pallaud, Celine; Mantzaris, Ioannis; Shastri, Aditi; Bussel, James B.; Verma, Amit K.; Steidl, Ulrich G.; Will, Britta.

In: Science Translational Medicine, Vol. 10, No. 458, eaas9563, 12.09.2018.

Research output: Contribution to journalArticle

Kao, Yun Ruei ; Chen, Jiahao ; Narayanagari, Swathi-Rao ; Todorova, Tihomira I. ; Aivalioti, Maria M. ; Ferreira, Mariana ; Ramos, Pedro M. ; Pallaud, Celine ; Mantzaris, Ioannis ; Shastri, Aditi ; Bussel, James B. ; Verma, Amit K. ; Steidl, Ulrich G. ; Will, Britta. / Thrombopoietin receptor-independent stimulation of hematopoietic stem cells by eltrombopag. In: Science Translational Medicine. 2018 ; Vol. 10, No. 458.
@article{a869ed7356ed46c796c84d3469c3faf3,
title = "Thrombopoietin receptor-independent stimulation of hematopoietic stem cells by eltrombopag",
abstract = "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.",
author = "Kao, {Yun Ruei} and Jiahao Chen and Swathi-Rao Narayanagari and Todorova, {Tihomira I.} and Aivalioti, {Maria M.} and Mariana Ferreira and Ramos, {Pedro M.} and Celine Pallaud and Ioannis Mantzaris and Aditi Shastri and Bussel, {James B.} and Verma, {Amit K.} and Steidl, {Ulrich G.} and Britta Will",
year = "2018",
month = "9",
day = "12",
doi = "10.1126/scitranslmed.aas9563",
language = "English (US)",
volume = "10",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "458",

}

TY - JOUR

T1 - Thrombopoietin receptor-independent stimulation of hematopoietic stem cells by eltrombopag

AU - Kao, Yun Ruei

AU - Chen, Jiahao

AU - Narayanagari, Swathi-Rao

AU - Todorova, Tihomira I.

AU - Aivalioti, Maria M.

AU - Ferreira, Mariana

AU - Ramos, Pedro M.

AU - Pallaud, Celine

AU - Mantzaris, Ioannis

AU - Shastri, Aditi

AU - Bussel, James B.

AU - Verma, Amit K.

AU - Steidl, Ulrich G.

AU - Will, Britta

PY - 2018/9/12

Y1 - 2018/9/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85053289698&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053289698&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.aas9563

DO - 10.1126/scitranslmed.aas9563

M3 - Article

C2 - 30209246

AN - SCOPUS:85053289698

VL - 10

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 458

M1 - eaas9563

ER -