Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors
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nihms867182.pdf
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Author(s)
Doulatov, Sergei
Vo, Linda T.
Macari, Elizabeth R.
Wahlster, Lara
Kinney, Melissa A.
Taylor, Alison M.
Barragan, Jessica
Gupta, Manav
McGrath, Katherine
Humphries, Jessica M.
Date Issued
February 2017
Journal
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Doulatov, Sergei et al. “Drug Discovery for Diamond-Blackfan Anemia Using Reprogrammed Hematopoietic Progenitors.” Science Translational Medicine 9, 376 (February 2017): eaah5645 © 2017 The Authors
Version
Author's final manuscript
Abstract
Diamond-Blackfan anemia (DBA) is a congenital disorder characterized by the failure of erythroid progenitor differentiation, severely curtailing red blood cell production. Because many DBA patients fail to respond to corticosteroid therapy, there is considerable need for therapeutics for this disorder. Identifying therapeutics for DBA requires circumventing the paucity of primary patient blood stem and progenitor cells. To this end, we adopted a reprogramming strategy to generate expandable hematopoietic progenitor cells from induced pluripotent stem cells (iPSCs) from DBA patients. Reprogrammed DBA progenitors recapitulate defects in erythroid differentiation, which were rescued by gene complementation. Unbiased chemical screens identified SMER28, a small-molecule inducer of autophagy, which enhanced erythropoiesis in a range of in vitro and in vivo models of DBA. SMER28 acted through autophagy factor ATG5 to stimulate erythropoiesis and up-regulate expression of globin genes. These findings present an unbiased drug screen for hematological disease using iPSCs and identify autophagy as a therapeutic pathway in DBA.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1126/SCITRANSLMED.AAH5645
