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

Abstract

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.