Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors.
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.
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.
Sergei
S
Doulatov
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.
Linda T
LT
Vo
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.
Elizabeth R
ER
Macari
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.
Lara
L
Wahlster
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.
Melissa A
MA
Kinney
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.
Alison M
AM
Taylor
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.
Jessica
J
Barragan
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.
Manav
M
Gupta
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.
Katherine
K
McGrath
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.|Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Hsiang-Ying
HY
Lee
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.
Jessica M
JM
Humphries
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.
Alex
A
DeVine
Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA.|Brigham and Women's Hospital, Boston, MA 02115, USA.
Anupama
A
Narla
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Blanche P
BP
Alter
Harvard Medical School, Boston, MA 02115, USA.|Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.|Manton Center for Orphan Disease Research, Boston, MA 02115, USA.
Alan H
AH
Beggs
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.|Manton Center for Orphan Disease Research, Boston, MA 02115, USA.
Suneet
S
Agarwal
Harvard Medical School, Boston, MA 02115, USA.|Brigham and Women's Hospital, Boston, MA 02115, USA.
Benjamin L
BL
Ebert
Harvard Medical School, Boston, MA 02115, USA.|Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.|Manton Center for Orphan Disease Research, Boston, MA 02115, USA.
Hanna T
HT
Gazda
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.|Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Harvey F
HF
Lodish
Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA.|Harvard Medical School, Boston, MA 02115, USA.
Colin A
CA
Sieff
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.
Thorsten M
TM
Schlaeger
Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA. george.daley@childrens.harvard.edu zon@enders.tch.harvard.edu.|Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA.|Harvard Medical School, Boston, MA 02115, USA.
Leonard I
LI
Zon
Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA. george.daley@childrens.harvard.edu zon@enders.tch.harvard.edu.|Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA.|Harvard Medical School, Boston, MA 02115, USA.|Manton Center for Orphan Disease Research, Boston, MA 02115, USA.
George Q
GQ
Daley
D000498:Allyl Compounds / Q000494:pharmacology; D029503:Anemia, Diamond-Blackfan / Q000188:drug therapy* / Q000473:pathology; D018952:Antigens, CD34 / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071187:Autophagy-Related Protein 5 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D065150:Cellular Reprogramming; D055808:Drug Discovery; D041905:Erythroid Cells / Q000187:drug effects / Q000473:pathology; D004920:Erythropoiesis / Q000187:drug effects; D005816:Genetic Complementation Test; D005914:Globins / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology
C560309:6-bromo-4-allylamino-quinazoline; D000498:Allyl Compounds; D018952:Antigens, CD34; D000071187:Autophagy-Related Protein 5; D011799:Quinazolines; D005914:Globins