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Open AccessArticle

Eltrombopag Improves Erythroid Differentiation in a Human Induced Pluripotent Stem Cell Model of Diamond Blackfan Anemia

1
Cellular and Molecular Therapeutics Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA
2
Department of Biology, Catholic University of America, Washington, DC 20064, USA
3
Department of Medical Laboratory Science, College of Applied Medical Sciences, The University of Hail, Hail 55476, Saudi Arabia
4
iPSC Core Facility, NHLBI, NIH, Bethesda, MD 20892, USA
5
Eunice Kennedy Shriver, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA
6
National Institute of General Medical Sciences (NIGMS), NIH, Bethesda, MD 20892, USA
7
Department of Medical Laboratories Technology, College of Applied Medical Sciences, Jazan University, Jazan 45142, Saudi Arabia
8
Clinical Flow Core Facility, NHLBI, NIH, Bethesda, MD 20892, USA
*
Author to whom correspondence should be addressed.
Academic Editor: James Adjaye
Cells 2021, 10(4), 734; https://doi.org/10.3390/cells10040734
Received: 7 January 2021 / Revised: 17 March 2021 / Accepted: 22 March 2021 / Published: 26 March 2021
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases)
Diamond Blackfan Anemia (DBA) is a congenital macrocytic anemia associated with ribosomal protein haploinsufficiency. Ribosomal dysfunction delays globin synthesis, resulting in excess toxic free heme in erythroid progenitors, early differentiation arrest, and pure red cell aplasia. In this study, DBA induced pluripotent stem cell (iPSC) lines were generated from blood mononuclear cells of DBA patients with inactivating mutations in RPS19 and subjected to hematopoietic differentiation to model disease phenotypes. In vitro differentiated hematopoietic cells were used to investigate whether eltrombopag, an FDA-approved mimetic of thrombopoietin with robust intracellular iron chelating properties, could rescue erythropoiesis in DBA by restricting the labile iron pool (LIP) derived from excessive free heme. DBA iPSCs exhibited RPS19 haploinsufficiency, reduction in the 40S/60S ribosomal subunit ratio and early erythroid differentiation arrest in the absence of eltrombopag, compared to control isogenic iPSCs established by CRISPR/Cas9-mediated correction of the RPS19 point mutation. Notably, differentiation of DBA iPSCs in the presence of eltrombopag markedly improved erythroid maturation. Consistent with a molecular mechanism based on intracellular iron chelation, we observed that deferasirox, a clinically licensed iron chelator able to permeate into cells, also enhanced erythropoiesis in our DBA iPSC model. In contrast, erythroid maturation did not improve substantially in DBA iPSC differentiation cultures supplemented with deferoxamine, a clinically available iron chelator that poorly accesses LIP within cellular compartments. These findings identify eltrombopag as a promising new therapeutic to improve anemia in DBA. View Full-Text
Keywords: diamond blackfan anemia; induced pluripotent stem cells; eltrombopag; genome editing; disease modeling; drug testing diamond blackfan anemia; induced pluripotent stem cells; eltrombopag; genome editing; disease modeling; drug testing
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MDPI and ACS Style

Qanash, H.; Li, Y.; Smith, R.H.; Linask, K.; Young-Baird, S.; Hakami, W.; Keyvanfar, K.; Choy, J.S.; Zou, J.; Larochelle, A. Eltrombopag Improves Erythroid Differentiation in a Human Induced Pluripotent Stem Cell Model of Diamond Blackfan Anemia. Cells 2021, 10, 734. https://doi.org/10.3390/cells10040734

AMA Style

Qanash H, Li Y, Smith RH, Linask K, Young-Baird S, Hakami W, Keyvanfar K, Choy JS, Zou J, Larochelle A. Eltrombopag Improves Erythroid Differentiation in a Human Induced Pluripotent Stem Cell Model of Diamond Blackfan Anemia. Cells. 2021; 10(4):734. https://doi.org/10.3390/cells10040734

Chicago/Turabian Style

Qanash, Husam; Li, Yongqin; Smith, Richard H.; Linask, Kaari; Young-Baird, Sara; Hakami, Waleed; Keyvanfar, Keyvan; Choy, John S.; Zou, Jizhong; Larochelle, Andre. 2021. "Eltrombopag Improves Erythroid Differentiation in a Human Induced Pluripotent Stem Cell Model of Diamond Blackfan Anemia" Cells 10, no. 4: 734. https://doi.org/10.3390/cells10040734

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