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
AU - Steidl, Ulrich
AU - Will, Britta
N1 - Funding Information:
We are thankful to W. Tong for providing Mpl-deficient mice and O. Abdel-Wahab for providing the mouse MPP cell line HPC7. We further thank D. Sun from the Einstein Stem Cell Isolation and Xenotransplantation Facility (funded through New York Stem Cell Science grant C029154) for expert assistance with flow cytometry and D. Reynolds and W. Tran from the Einstein Genomics Core Facility for help with the microarray experiments. For metabolite profiling assays, we thank Y. Qiu and I. Kurland from the Stable Isotope and Metabolomics Core Facility of the Einstein-Mount Sinai Diabetes Research Center of the Albert Einstein College of Medicine (supported by NIH/National Cancer Institute grant P60DK020541) for expert support. We also thank P. Schultes from the Department of Cell Biology at Albert Einstein College of Medicine for expert technical assistance. We thank the team members of the Will and Steidl laboratories, as well as M. Roth for helpful discussions. Funding: This work was supported by K01DK105134 (to B.W.), P30CA013330 (pilot grant; to B.W.), R01CA166429 (to U.S.), R01CA217092 (to U.S.), and the Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund through New York State Department of Health Contract C30292GG (to J.C. and M.M.A.). U.S. is a research scholar of the Leukemia and Lymphoma Society and the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research of the Albert Einstein College of Medicine. Author contributions: B.W. and U.S. designed the research. Y.-R.K. and B.W. designed the experiments. Y.-R.K., J.C., S.-R.N., T.I.T., M.M.A., and M.F. performed the experiments. Y.-R.K. and J.C. performed the biocomputational analysis of data. All authors interpreted the data. J.B.B., A.S., I.M., and A.V. provided the patient specimen. Y.-R.K. and B.W. wrote the manuscript. Competing interests: B.W, U.S., and A.V. have received research support from GlaxoSmithKline and Novartis Pharmaceuticals. B.W., U.S., and A.V. have served as consultants for Novartis Pharmaceuticals. P.M.R. and C.P. are employees of Novartis Pharmaceuticals. J.B.B. has served as a consultant on advisory medical and scientific boards for Amgen, Novartis, Rigel, Momenta, and Union Chimique Belge (U.C.B.). Although J.B.B. has been consulting for Novartis and Rigel, he has had no role in arranging purchases of pharmaceuticals. Data and materials availability: All data associated with this study are present in the paper or the Supplementary Materials. Gene expression microarray data for this study have been deposited in Gene Expression Omnibus database with accession number GSE107430.
Publisher Copyright:
Copyright © 2018 The Authors.
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.
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U2 - 10.1126/scitranslmed.aas9563
DO - 10.1126/scitranslmed.aas9563
M3 - Article
C2 - 30209246
AN - SCOPUS:85053289698
SN - 1946-6234
VL - 10
JO - Science translational medicine
JF - Science translational medicine
IS - 458
M1 - eaas9563
ER -