| Literature DB >> 28179501 |
Sergei Doulatov1,2, Linda T Vo1,2, Elizabeth R Macari1,2, Lara Wahlster1,2, Melissa A Kinney1,2, Alison M Taylor1,2,3, Jessica Barragan1,2, Manav Gupta1,2, Katherine McGrath1,2, Hsiang-Ying Lee4,5, Jessica M Humphries1,2, Alex DeVine1,2, Anupama Narla2,6, Blanche P Alter7, Alan H Beggs3,8,9, Suneet Agarwal1,2,3,9, Benjamin L Ebert3,6, Hanna T Gazda3,8,9, Harvey F Lodish4,5, Colin A Sieff2,3, Thorsten M Schlaeger1,2, Leonard I Zon10,2,3, George Q Daley10,2,3,9.
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.Entities:
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Year: 2017 PMID： 28179501 PMCID： PMC5501179 DOI： 10.1126/scitranslmed.aah5645
Source DB: PubMed Journal: Sci Transl Med ISSN： 1946-6234 Impact factor: 17.956