The role of epigenetics in the induction of fetal hemoglobin: a combination therapy approach.

BACKGROUND: ß-thalassemia considers worldwide public health disorders. Novel fetal hemoglobin inducer agents such as thalidomide and sodium butyrate have been attended for ameliorating clinical complications of such disorders. MATERIAL AND METHODS: We used thalidomide and sodium butyrate for increasing the level of fetal hemoglobin in erythroid progenitors. Briefly, after isolation of CD133+ stem cells from umbilical cord blood and differentiation into erythroid lineage, erythroid progenitors were treated with thalidomide and sodium butyraye as single and combination. H3K4 histone methylation was evaluated following fetal hemoglobin induction using chromatin immuno percipitation (ChIP) technique. RESULTS: The results of this study showed that the effect of thalidomide on increasing of H3K4 methylation was highest compared to sodium butyrate and combination of both agents (p < 0.05). CONCLUSION: Consequently, our study of the epigenetic modification of the γ-globin suggests that histone H3K4 dimethylation are significant for the regulation of developmental stage-specific expression of the γ-globin genes.

Evaluation of H3 histone methylation and colony formation in erythroid progenitors treated with thalidomide and sodium butyrate.

OBJECTIVES: ß-thalassemia and sickle cell disease are hemoglobinopathies with reduced/absent ß chains in the former and dysfunctional ß chains in the latter. In both conditions, up-regulation of hemoglobin F through demethylation can alleviate the symptoms. This can be attained with drugs such as thalidomide and sodium butyrate. MATERIALS AND METHODS: This study was performed on erythroid progenitors derived from CD133+ cord blood stem cells. Erythroid progenitors were treated with thalidomide and sodium butyrate in single and combined groups. Colony-formation potential in each group was evaluated by the colony assay. Real-time polymerase chain reaction (RT-PCR) was used to evaluate the effect of these drugs on histone H3 lysine 27 (H3K27) methylation patterns. FINDINGS: Compared to other treatment groups, CD133+ cells treated with thalidomide alone produced more hematopoietic colonies. Thalidomide alone was also more effective in decreasing H3K27 methylation. CONCLUSIONS: Thalidomide shows superiority to sodium butyrate as a hypomethylating agent in this cell culture study, and it has the potential to become conventional treatment for sickle cell disease and ß-thalassemia.

Evaluation of Signaling Pathways Involved in γ-Globin Gene Induction Using Fetal Hemoglobin Inducer Drugs.

Potent induction of fetal hemoglobin (HbF) production results in alleviating the complications of ß-thalassemia and sickle cell disease (SCD). HbF inducer agents can trigger several molecular signaling pathways critical for erythropoiesis. Janus kinase/Signal transducer and activator of transcription (JAK/STAT), mitogen activated protein kinas (MAPK) and Phosphoinositide 3-kinase (PI3K) are considered as main signaling pathways, which may play a significant role in HbF induction. All these signaling pathways are triggered by erythropoietin (EPO) as the main growth factor inducing erythroid differentiation, when it binds to its cell surface receptor, erythropoietin receptor (EPO-R) HbF inducer agents have been shown to upregulate HbF production level by triggering certain signaling pathways. As a result, understanding the pivotal signaling pathways influencing HbF induction leads to effective upregulation of HbF. In this mini review article, we try to consider the correlation between HbF inducer agents and their molecular mechanisms of γ-globin upregulation. Several studies suggest that activating P38 MAPK, RAS and STAT5 signaling pathways result in efficient HbF induction. Nevertheless, the role of other erythroid signaling pathways in HbF induction seems to be indispensible and should be emphasized.

Evaluation of Novel Fetal Hemoglobin Inducer Drugs in Treatment of ß-Hemoglobinopathy Disorders.

OBJECTIVE: The use of fetal hemoglobin (HbF) inducer drugs is considered as a novel approach in treatment of ß-hemoglobinopathies, especially ß- thalassemia and sickle cell disease. HbF inducers including hydroxyurea, histone deacetylase (HDAC) inhibitor agents such as sodium butyrate, azacitidine, decitabine and new immunomodulator drugs like pomalidomide, lenalidomide and thalidomide can reduce α-globin chain production in erythroid progenitors and improve α: ß chain imbalance, the most crucial complication of ß-thalassemia. MATERIALS AND METHODS: In this article, we reviewed more than 40 articles published from 1979 to 2012 in the field of fetal hemoglobin augmentation. RESULTS: Recent studies suggest the synergistic effect of drug combinations in efficient induction of fetal hemoglobin and gene over-expression. CONCLUSION: It seems that drugs which act with different molecular and epigenetic mechanisms have proper synergistic effects in fetal hemoglobin induction and gene over-expression.