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Sci Transl Med. 2017 Feb 8;9(376). pii: eaah5645. doi: 10.1126/scitranslmed.aah5645.

Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors.

Doulatov S1,2, Vo LT1,2, Macari ER1,2, Wahlster L1,2, Kinney MA1,2, Taylor AM1,2,3, Barragan J1,2, Gupta M1,2, McGrath K1,2, Lee HY4,5, Humphries JM1,2, DeVine A1,2, Narla A2,6, Alter BP7, Beggs AH3,8,9, Agarwal S1,2,3,9, Ebert BL3,6, Gazda HT3,8,9, Lodish HF4,5, Sieff CA2,3, Schlaeger TM1,2, Zon LI10,2,3, Daley GQ10,2,3,9.

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Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA.
Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA.
Harvard Medical School, Boston, MA 02115, USA.
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Brigham and Women's Hospital, Boston, MA 02115, USA.
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
Manton Center for Orphan Disease Research, Boston, MA 02115, USA.
Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA.


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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