Lysine-specific demethylase 1 is a therapeutic target for fetal hemoglobin induction

• Published in: Nature medicine Vol. 19; no. 3; pp. 291 - 294
• Main Authors: Shi, Lihong, Cui, Shuaiying, Engel, James D, Tanabe, Osamu
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-03-2013; Nature Publishing Group
• Subjects: 692/699/1541; 692/699/1541/13; 692/700/565/1436/2185; Anemia, Sickle Cell - genetics; Anemia, Sickle Cell - therapy; Animals; beta-Globins - genetics; beta-Thalassemia - genetics; beta-Thalassemia - therapy; Biomedicine; brief-communication; Cancer Research; Care and treatment; Cell Differentiation; Cells, Cultured; Epigenetics; Erythroid Cells - drug effects; Erythroid Cells - metabolism; Fetal Hemoglobin - biosynthesis; gamma-Globins - biosynthesis; Gene expression; Genetic aspects; Health aspects; Hemoglobin; Hemoglobinopathy; Histone Demethylases - antagonists & inhibitors; Histone Demethylases - genetics; Histone Demethylases - metabolism; Humans; Infectious Diseases; Inhibitor drugs; Lysine; Metabolic Diseases; Mice; Mice, Transgenic; Molecular Medicine; Molecular Targeted Therapy; Monoamine Oxidase Inhibitors - pharmacology; Neurosciences; Nuclear Receptor Subfamily 2, Group C, Member 1 - metabolism; Oxidases; Pharmacology; Physiological aspects; Promoter Regions, Genetic; Receptors, Steroid - metabolism; Receptors, Thyroid Hormone - metabolism; Risk factors; RNA Interference; RNA, Small Interfering; Tranylcypromine - pharmacology; Japan
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3101

Patients with sickle cell disease or β-thalassemia are treated with drugs that aim to reactivate production of fetal hemoglobin, but these drugs are not effective in all patients and have side effects. Lihong Shi
et al
. identify a new therapeutic strategy for these anemias, showing that a drug used to treat depression, tranylcypromine, can raise fetal hemoglobin levels in human erythroid cells and transgenic mice harboring the human β-globin locus, most likely by inhibiting a lysine demethylase that controls fetal globin gene expression.
Enhanced fetal γ-globin synthesis alleviates symptoms of β-globinopathies such as sickle cell disease and β-thalassemia, but current γ-globin–inducing drugs offer limited beneficial effects. We show here that lysine-specific demethylase 1 (LSD1) inhibition by RNAi in human erythroid cells or by the monoamine oxidase inhibitor tranylcypromine in human erythroid cells or β-type globin–transgenic mice enhances γ-globin expression. LSD1 is thus a promising therapeutic target for γ-globin induction, and tranylcypromine may serve as a lead compound for the development of a new γ-globin inducer.