Modulation of gamma globin genes expression by histone deacetylase inhibitors: An in vitro study

Luisa Ronzoni, Laura Sonzogni, Gianluca Fossati, Daniela Modena, Elena Trombetta, Laura Porretti, Maria Domenica Cappellini

Research output: Contribution to journalArticle

Abstract

Induction of fetal haemoglobin (HbF) is a promising therapeutic approach for the treatment of β-thalassaemia and sickle cell disease (SCD). Several pharmacological agents, such as hydroxycarbamide (HC) and butyrates, have been shown to induce the γ-globin genes (HBG1, HBG2). However, their therapeutic use is limited due to weak efficacy and an inhibitory effect on erythroid differentiation. Thus, more effective agents are needed. The histone deacetylase (HDAC) inhibitors are potential therapeutic haemoglobin (Hb) inducers able to modulate gene expression through pleiotropic mechanisms. We investigated the effects of a HDAC inhibitor, Givinostat (GVS), on erythropoiesis and haemoglobin synthesis and compared it with sodium butyrate and HC. We used an in vitro erythropoiesis model derived from peripheral CD34+ cells of healthy volunteers and SCD donors. GVS effects on erythroid proliferation and differentiation and on Hb synthesis were investigated. We found that GVS at high concentrations delayed erythroid differentiation with no specific effect on HBG1/2 transcription. At a low concentration (1 nmol/l), GVS induced Hb production with no effects on cells proliferation and differentiation. The efficacy of GVS 1 mol/l in Hb induction in vitro was comparable to that of HC and butyrate. Our results support the evaluation of GVS as a new candidate molecule for the treatment of the haemoglobinophathies due to its positive effects on haemoglobin production at low and non-toxic concentrations.

Original languageEnglish
Pages (from-to)714-721
Number of pages8
JournalBritish Journal of Haematology
Volume165
Issue number5
DOIs
Publication statusPublished - 2014

Keywords

  • Fetal haemoglobin induction
  • Globin gene transcription
  • Histone deacetylase inhibitor
  • Sickle cell disease
  • β-thalassaemia

ASJC Scopus subject areas

  • Hematology
  • Medicine(all)

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