title: The LSD1 inhibitor RN-1 induces fetal hemoglobin synthesis and reduces disease pathology in sickle cell mice.
abstract: Inhibition of lysine-specific demethylase 1 (LSD1) has been shown to induce fetal hemoglobin (HbF) levels in cultured human erythroid cells in vitro. Here we report the in vivo effects of LSD1 inactivation by a selective and more potent inhibitor, RN-1, in a sickle cell disease (SCD) mouse model. Compared with untreated animals, RN-1 administration leads to induced HbF synthesis and to increased frequencies of HbF-positive cells and mature erythrocytes, as well as fewer reticulocytes and sickle cells, in the peripheral blood of treated SCD mice. In keeping with these observations, histologic analyses of the liver and spleen of treated SCD mice verified that they do not exhibit the necrotic lesions that are usually associated with SCD. These data indicate that RN-1 can effectively induce HbF levels in red blood cells and reduce disease pathology in SCD mice, and may therefore offer new therapeutic possibilities for treating SCD.
authors.affiliation: Department of Cell and Developmental Biology.
authors.forename: Shuaiying
authors.identifier: http://orcid.org/0000-0001-9104-8517
authors.initials: S
authors.lastname: Cui
authors.affiliation: Department of Cell and Developmental Biology.
authors.forename: Kim-Chew
authors.initials: KC
authors.lastname: Lim
authors.affiliation: Department of Cell and Developmental Biology.
authors.forename: Lihong
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Cell and Developmental Biology.
authors.forename: Mary
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Cell and Developmental Biology.
authors.forename: Natee
authors.initials: N
authors.lastname: Jearawiriyapaisarn
authors.affiliation: Department of Cell and Developmental Biology.
authors.forename: Greggory
authors.initials: G
authors.lastname: Myers
authors.affiliation: Department of Pediatrics and Infectious Diseases.
authors.forename: Andrew
authors.initials: A
authors.lastname: Campbell
authors.affiliation: Department of Pathology.
authors.forename: David
authors.initials: D
authors.lastname: Harro
authors.affiliation: Department of Human Genetics, and.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Iwase
authors.affiliation: Department of Biological Chemistry, University of Michigan, Ann Arbor, MI;
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Trievel
authors.affiliation: Jesse Brown VA Medical Center, Department of Pediatrics, and.
authors.forename: Angela
authors.initials: A
authors.lastname: Rivers
authors.affiliation: Department of Pediatrics, and Department of Medicine, University of Illinois at Chicago, Chicago, IL; and.
authors.forename: Joseph
authors.initials: J
authors.lastname: DeSimone
authors.affiliation: Department of Pediatrics, and Department of Medicine, University of Illinois at Chicago, Chicago, IL; and.
authors.forename: Donald
authors.initials: D
authors.lastname: Lavelle
authors.affiliation: Cleveland Clinic, Cleveland, OH.
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
authors.affiliation: Department of Cell and Developmental Biology.
authors.forename: James Douglas
authors.initials: JD
authors.lastname: Engel
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005319:Fetal Hemoglobin / Q000096:biosynthesis* / Q000187:drug effects; D005434:Flow Cytometry; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012235:Rhodamines / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*; D013163:Splenomegaly / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D013876:Thiophenes / Q000494:pharmacology*; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism
chemical_list: C547335:RN1 compound; D012333:RNA, Messenger; D012235:Rhodamines; D013141:Spiro Compounds; D013876:Thiophenes; D055544:beta-Globins; D005319:Fetal Hemoglobin; D056466:Histone Demethylases; C504076:KDM1a protein, mouse