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iPSC modeling of severe aplastic anemia reveals impaired differentiation and telomere shortening in blood progenitors.

Melguizo-Sanchis, Dario and Xu, Yaobo and Taheem, Dheraj and Yu, Min and Tilgner, Katarzyna and Barta, Tomas and Gassner, Katja and Anyfantis, George and Wan, Tengfei and Elango, Ramu and Alharthi, Sameer and El-Harouni, Ashraf A. and Przyborski, Stefan and Adam, Soheir and Saretzki, Gabriele and Samarasinghe, Sujith and Armstrong, Lyle and Lako, Majlinda (2018) 'iPSC modeling of severe aplastic anemia reveals impaired differentiation and telomere shortening in blood progenitors.', Cell death and disease., 9 (2). p. 128.


Aplastic Anemia (AA) is a bone marrow failure (BMF) disorder, resulting in bone marrow hypocellularity and peripheral pancytopenia. Severe aplastic anemia (SAA) is a subset of AA defined by a more severe phenotype. Although the immunological nature of SAA pathogenesis is widely accepted, there is an increasing recognition of the role of dysfunctional hematopoietic stem cells in the disease phenotype. While pediatric SAA can be attributable to genetic causes, evidence is evolving on previously unrecognized genetic etiologies in a proportion of adults with SAA. Thus, there is an urgent need to better understand the pathophysiology of SAA, which will help to inform the course of disease progression and treatment options. We have derived induced pluripotent stem cell (iPSC) from three unaffected controls and three SAA patients and have shown that this in vitro model mimics two key features of the disease: (1) the failure to maintain telomere length during the reprogramming process and hematopoietic differentiation resulting in SAA-iPSC and iPSC-derived-hematopoietic progenitors with shorter telomeres than controls; (2) the impaired ability of SAA-iPSC-derived hematopoietic progenitors to give rise to erythroid and myeloid cells. While apoptosis and DNA damage response to replicative stress is similar between the control and SAA-iPSC-derived-hematopoietic progenitors, the latter show impaired proliferation which was not restored by eltrombopag, a drug which has been shown to restore hematopoiesis in SAA patients. Together, our data highlight the utility of patient specific iPSC in providing a disease model for SAA and predicting patient responses to various treatment modalities.

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Publisher statement:Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
Date accepted:10 November 2017
Date deposited:15 February 2018
Date of first online publication:26 January 2018
Date first made open access:15 February 2018

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