Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 9, Issue 376, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aah5645
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Funding
- NIH National Institute of Diabetes and Digestive and Kidney Diseases [R24-DK092760, R24-DK49216, U54DK110805]
- National Heart, Lung, and Blood Institute (NHLBI) Progenitor Cell Biology Consortium [UO1-HL100001, U01HL134812]
- NHLBI [R01HL04880, 1K99HL123484, R00HL123484-03, R01HL107558]
- NIH [R24OD017870-01, K02HL111156]
- Alex's Lemonade Stand Foundation
- Taub Foundation Grants Program for MDS Research
- Doris Duke Medical Foundation
- Division of Cancer Epidemiology and Genetics, NCI, NIH
- Helen Hay Whitney Foundation
- NSF Graduate Research Fellowship
- NIH NHLBI [1F32HL124948-01]
- University of Heidelberg Medical School
- Brigham and Women's Hospital
- Charles H. Hood Foundation
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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.
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