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

Abstract

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.

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Figure 1: Induction of fetal hemoglobin by an LSD1 inhibitor, TCP, in adult erythroid cells.
Figure 2: Induction of γ-globin expression by LSD1 inhibition.

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Acknowledgements

This work was supported by US National Institutes of Health grants DK086956 (to O.T. and J.D.E.) and HL24415 (to J.D.E.) and an American Heart Association postdoctoral fellowship to L.S. We thank D. Giacherio and D. Harro for hemoglobin HPLC analysis; C. Yu, A.D. Campbell, K.C. Lim, T. Hosoya, B. Godfrey and M. Sierant for discussions, comments and technical assistance; and D. Lavelle and J. DeSimone for discussions regarding the inductive properties of decitabine. Lentiviruses were produced by the University of Michigan Vector Core. Microarray analysis was performed at the University of Michigan Microarray Core.

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O.T. and J.D.E. conceived of the study; L.S., S.C., J.D.E. and O.T. designed experiments. L.S. and S.C. performed experiments. L.S., S.C., J.D.E. and O.T. analyzed data and wrote the paper.

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Correspondence to James D Engel or Osamu Tanabe.

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The authors declare no competing financial interests.

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Supplementary Figures 1–9 and Supplementary Tables 1–4 (PDF 2950 kb)

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Shi, L., Cui, S., Engel, J. et al. Lysine-specific demethylase 1 is a therapeutic target for fetal hemoglobin induction. Nat Med 19, 291–294 (2013). https://doi.org/10.1038/nm.3101

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