Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors

• Published in: Science translational medicine Vol. 9; no. 376
• Main Authors: Doulatov, Sergei, Vo, Linda T, Macari, Elizabeth R, Wahlster, Lara, Kinney, Melissa A, Taylor, Alison M, Barragan, Jessica, Gupta, Manav, McGrath, Katherine, Lee, Hsiang-Ying, Humphries, Jessica M, DeVine, Alex, Narla, Anupama, Alter, Blanche P, Beggs, Alan H, Agarwal, Suneet, Ebert, Benjamin L, Gazda, Hanna T, Lodish, Harvey F, Sieff, Colin A, Schlaeger, Thorsten M, Zon, Leonard I, Daley, George Q
• Format: Journal Article
• Language: English
• Published: United States 08.02.2017
• Subjects: Allyl Compounds - pharmacology; Anemia, Diamond-Blackfan - drug therapy; Anemia, Diamond-Blackfan - pathology; Antigens, CD34 - metabolism; Autophagy - drug effects; Autophagy-Related Protein 5 - metabolism; Cell Differentiation - drug effects; Cellular Reprogramming; Drug Discovery; Erythroid Cells - drug effects; Erythroid Cells - pathology; Erythropoiesis - drug effects; Genetic Complementation Test; Globins - metabolism; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Humans; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - metabolism; Quinazolines - pharmacology
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.aah5645

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.