RN-1, a potent and selective lysine-specific demethylase 1 inhibitor, increases γ-globin expression, F reticulocytes, and F cells in a sickle cell disease mouse model.
Increased levels of fetal hemoglobin are associated with decreased symptoms and increased lifespan in patients with sickle cell disease (SCD). Hydroxyurea, the only drug currently approved for SCD, is not effective in a large fraction of patients, and therefore, new agents are urgently needed. Recently it was found that lysine demethylase 1, an enzyme that removes monomethyl and dimethyl residues from the lysine 4 residue of histone H3, is a repressor of γ-globin gene expression. In this article, we have compared the ability of tranylcypromine (TCP) and a more potent TCP derivative, RN-1, to increase γ-globin expression in cultured baboon erythroid progenitor cells and in the SCD mouse model. The results indicate that the ability of RN-1 to induce F cells and γ-globin mRNA in SCD mice is similar to that of decitabine, the most powerful fetal hemoglobin-inducing drug known, and greater than that of either TCP or hydroxyurea. We conclude that RN-1 and other lysine demethylase 1 inhibitors may be promising new γ-globin-inducing agents for the treatment of SCD that warrant further studies in other preclinical models, such as nonhuman primates.
Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA; Jesse Brown VA Medical Center, Chicago, IL, USA. Electronic address: riversa@uic.edu.
Angela
A
Rivers
Jesse Brown VA Medical Center, Chicago, IL, USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Kestis
K
Vaitkus
Jesse Brown VA Medical Center, Chicago, IL, USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Maria Armila
MA
Ruiz
Jesse Brown VA Medical Center, Chicago, IL, USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Vinzon
V
Ibanez
Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA; Jesse Brown VA Medical Center, Chicago, IL, USA.
Ramasamy
R
Jagadeeswaran
Jesse Brown VA Medical Center, Chicago, IL, USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Tatiana
T
Kouznetsova
Jesse Brown VA Medical Center, Chicago, IL, USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Joseph
J
DeSimone
Jesse Brown VA Medical Center, Chicago, IL, USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Donald
D
Lavelle
D000755:Anemia, Sickle Cell / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects; D005319:Fetal Hemoglobin / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D010215:Papio; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012156:Reticulocytes / Q000187:drug effects*; D019076:Transgenes / Q000187:drug effects; D014191:Tranylcypromine / Q000031:analogs & derivatives / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology; D020298:U937 Cells; D055545:gamma-Globins / Q000096:biosynthesis* / Q000235:genetics
D004791:Enzyme Inhibitors; D006657:Histones; D055545:gamma-Globins; D014191:Tranylcypromine; D014212:Tretinoin; D005319:Fetal Hemoglobin; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D006918:Hydroxyurea