iPSC modeling of severe aplastic anemia reveals impaired differentiation and telomere shortening in blood progenitors.
Abstract
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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https://hdl.handle.net/10161/19060Published Version (Please cite this version)
10.1038/s41419-017-0141-1Publication Info
Melguizo-Sanchis, Dario; Xu, Yaobo; Taheem, Dheraj; Yu, Min; Tilgner, Katarzyna; Barta,
Tomas; ... Lako, Majlinda (2018). iPSC modeling of severe aplastic anemia reveals impaired differentiation and telomere
shortening in blood progenitors. Cell death & disease, 9(2). pp. 128. 10.1038/s41419-017-0141-1. Retrieved from https://hdl.handle.net/10161/19060.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Soheir Saeed Adam
Associate Professor of Medicine

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