Abstract
β-Thalassaemia is one of the most common monogenic diseases with no effective cure in the majority of patients. Unbalanced production of α-globin in the presence of defective synthesis of β-globin is the primary mechanism for anaemia in β-thalassaemia. Clinical genetic data accumulated over three decades have clearly demonstrated that direct suppression of α-globin and induction of γ-globin are effective in reducing the globin chain imbalance in erythroid cells hence improving the clinical outcome of patients with β-thalassaemia. Here, we show that the histone deacetylase inhibitor drug, vorinostat, in addition to its beneficial effects for patients with β-thalassaemia through induction of γ-globin, has the potential to simultaneously suppress α-globin. We further show that vorinostat exhibits these synergistic beneficial effects in globin gene expression at nanomolar concentrations without perturbing erythroid expansion, viability, differentiation or the transcriptome. This new evidence will be helpful for the interpretation of existing clinical trials and future clinical studies that are directed towards finding a cure for β-thalassaemia using vorinostat.
Highlights
Sachith Mettananda[1,2], Nirmani Yasara[1], Christopher A
The molecular defects causing β-thalassemia are point mutations predominantly found within and around the β-globin gene which result in reduced or absent synthesis of β-globin[10]. This unbalanced production of α- and β-like globin chains leads to precipitation of free α-globin chains in red blood cells (RBC) and their precursors to cause haemolysis and ineffective erythropoiesis which are considered as the primary pathophysiological mechanism for the anaemia in thalassaemia[11]
We previously performed a small molecule screen using Fluidigm high throughput Quantitative polymerase chain reaction (qPCR) platform to identify compounds that alter globin gene expression in human erythroid cells to identify compounds that produce favourable effects for β-thalassaemia. This screen identified several promising compounds that down regulate α-globin expression of which IOX1, a broad-spectrum histone demethylase inhibitor was studied in depth[17]. Subsequent analysis of this small molecule screen identified a number of histone deacetylase (HDAC) inhibitor drugs which upregulate γ-globin expression in human erythroid cells (Supplemental Table 1)
Summary
Sachith Mettananda[1,2], Nirmani Yasara[1], Christopher A. We further show that vorinostat exhibits these synergistic beneficial effects in globin gene expression at nanomolar concentrations without perturbing erythroid expansion, viability, differentiation or the transcriptome This new evidence will be helpful for the interpretation of existing clinical trials and future clinical studies that are directed towards finding a cure for β-thalassaemia using vorinostat. The molecular defects causing β-thalassemia are point mutations predominantly found within and around the β-globin gene which result in reduced or absent synthesis of β-globin[10] This unbalanced production of α- and β-like globin chains leads to precipitation of free α-globin chains in red blood cells (RBC) and their precursors to cause haemolysis and ineffective erythropoiesis which are considered as the primary pathophysiological mechanism for the anaemia in thalassaemia[11]. We show that vorinostat directly reduces the production of α-globin whilst inducing the expression of γ-globin in human erythroid cells without perturbing erythroid proliferation, viability, differentiation or global gene expression
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