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 language | English |
|---|---|
| Pages (from-to) | 714-721 |
| Number of pages | 8 |
| Journal | British Journal of Haematology |
| Volume | 165 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2014 |
Fingerprint
Keywords
- Fetal haemoglobin induction
- Globin gene transcription
- Histone deacetylase inhibitor
- Sickle cell disease
- β-thalassaemia
ASJC Scopus subject areas
- Hematology
- Medicine(all)
Cite this
Modulation of gamma globin genes expression by histone deacetylase inhibitors : An in vitro study. / Ronzoni, Luisa; Sonzogni, Laura; Fossati, Gianluca; Modena, Daniela; Trombetta, Elena; Porretti, Laura; Cappellini, Maria Domenica.
In: British Journal of Haematology, Vol. 165, No. 5, 2014, p. 714-721.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Modulation of gamma globin genes expression by histone deacetylase inhibitors
T2 - An in vitro study
AU - Ronzoni, Luisa
AU - Sonzogni, Laura
AU - Fossati, Gianluca
AU - Modena, Daniela
AU - Trombetta, Elena
AU - Porretti, Laura
AU - Cappellini, Maria Domenica
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Fetal haemoglobin induction
KW - Globin gene transcription
KW - Histone deacetylase inhibitor
KW - Sickle cell disease
KW - β-thalassaemia
UR - http://www.scopus.com/inward/record.url?scp=84900498831&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84900498831&partnerID=8YFLogxK
U2 - 10.1111/bjh.12814
DO - 10.1111/bjh.12814
M3 - Article
C2 - 24606390
AN - SCOPUS:84900498831
VL - 165
SP - 714
EP - 721
JO - British Journal of Haematology
JF - British Journal of Haematology
SN - 0007-1048
IS - 5
ER -