A study of the histone deacetylase inhibitor effects on the fetal hemoglobin induction and erythropoiesis in β-thalassemia
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Issued Date
2021
Resource Type
Language
eng
File Type
application/pdf
No. of Pages/File Size
xv, 103 leaves : ill.
Access Rights
open access
Rights
ผลงานนี้เป็นลิขสิทธิ์ของมหาวิทยาลัยมหิดล ขอสงวนไว้สำหรับเพื่อการศึกษาเท่านั้น ต้องอ้างอิงแหล่งที่มา ห้ามดัดแปลงเนื้อหา และห้ามนำไปใช้เพื่อการค้า
Rights Holder(s)
Mahidol University
Bibliographic Citation
Thesis (M.Sc. (Medical Biochemistry and Molecular Biology))--Mahidol University, 2021
Suggested Citation
Pawarit Innachai A study of the histone deacetylase inhibitor effects on the fetal hemoglobin induction and erythropoiesis in β-thalassemia. Thesis (M.Sc. (Medical Biochemistry and Molecular Biology))--Mahidol University, 2021. Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/113796
Title
A study of the histone deacetylase inhibitor effects on the fetal hemoglobin induction and erythropoiesis in β-thalassemia
Author(s)
Abstract
Fetal hemoglobin (HbF; α2γ2) induction can alleviate the clinical severity of the patients with β-hemoglobinopathies such as β-thalassemia and sickle cell disease. Epigenetic modifications partly regulate gene expression including globin genes. Histone deacetylases (HDACs) are the epigenetic modifying enzymes, which have been investigated as potential therapeutic targets for HbF induction in β-hemoglobinopathies. Inhibition of HDAC can induce HbF expression in erythroleukemic cell lines and hematopoietic progenitor cells. In this study, the effects of six HDAC inhibitors were investigated in human erythroid progenitor cells. Of these, entinostat was revealed HbF-inducing activityin erythroid progenitor cells derived from healthy donors and β-thalassemia/HbE patients.Treatment with entinostat at 500 nM led to 1.5 ± 0.5 folds increase in levels of γ-globin mRNA and approximately 10% increase of HbF level; HbF = 38.8 ± 6.4% in treated cells versus 32.0 ± 6.3% in untreated control, without significant alteration in cell differentiation. Higher expression of γ-globin transcript and HbF levels were observed in cells treated with entinostat at 1000 nM, but inhibition of cell proliferation was also revealed. A slight increase of HbF level exhibited in erythroid cells treated with entinostat at 100 nM. Similar effects on HbF production and erythropoiesis were found in healthy donor-derived erythroid cells treated with entinostat. These findings indicate that entinostat has potential as a HbF-induction agent for β-thalassemias and could be of interest in developing a treatment for patients with β-thalassemia. However, appropriate dose titration and time-course of this compound must be further investigated for HbF induction and cell proliferation. In addition, the effect of entinostat on the expression level of twelve erythroid transcription factors was investigated using quantitative RT-PCR analysis. The results revealed that the level of GATA2 transcript was increased in erythroid cells treated with entinostat, but LRF transcript was decreased in treated cells, whereas other erythroid regulators were unaffected. These expression changes were observed in both healthy donor and β-thalassemia/HbE patient-derived erythroid cells. The findings suggested that increase expressions of the γ-globingene and production of HbF in entinostat treated cells may indirectly involve with dynamic expression of GATA2 and LRF, which deserves further investigations. Altogether, inhibition of HDAC by entinostat induces the HbF production in β-thalassemia/HbE erythroid progenitor cells, supporting further evaluation to clinical application of entinostat in the treatment of β-thalassemia patients.
Description
Medical Biochemistry and Molecular Biology (Mahidol University 2021)
Degree Name
Master of Science
Degree Level
Masters
Degree Department
Faculty of Medicine Siriraj Hospital
Degree Discipline
Medical Biochemistry and Molecular Biology
Degree Grantor(s)
Mahidol University