期刊
HEMATOLOGY REPORTS
卷 13, 期 4, 页码 -出版社
PAGEPRESS PUBL
DOI: 10.4081/hr.2021.9215
关键词
Thalassemia; Erythroid; Fetal hemoglobin; LSD1; RN-1
类别
资金
- Mahidol University
- Thailand Research Funding
- Office of the Higher Education Commission, Thailand
- Thailand Research Funding [PHD/0092/2556]
The use of LSD1 inhibitor RN-1 significantly increases gamma-globin transcript and HbF expression levels in erythroid cells derived from beta(0)-thalassemia/HbE patients, without affecting cell viability and proliferation at low concentration, but leading to decreased cell numbers at high concentration.
Induction of fetal hemoglobin (HbF) ameliorates the clinical severity of beta-thalassemias. Histone methyltransferase LSD1 enzyme removes methyl groups from the activating chromatin mark histone 3 lysine 4 at silenced genes, including the gamma-globin genes. LSD1 inhibitor RN-1 induces HbF levels in cultured human erythroid cells. Here, the HbF-inducing activity of RN-1 was investigated in erythroid progenitor cells derived from beta(0)-thalassemia/ hemoglobin E (HbE) patients. The significant and reproducible increases in gamma-globin transcript and HbF expression upon RN-1 treatment were demonstrated in erythroid cells with divergent HbF baseline levels, the average of HbF induction was 17.7 +/- 0.8%. RN-1 at low concentration did not affect viability and proliferation of erythroid cells, but decreases in cell number were observed in cells treated with RN- 1 at high concentration. Delayed terminal erythroid differentiation was revealed in beta(0)-thalassemia/HbE erythroid cells treated with RN-1 as similar to other compounds that target LSD1 activity. Downregulation of repressors of gamma-globin expression; NCOR1 and SOX6, was observed in RN-1 treatment. These findings provide proof of the concept that LSD1 epigenetic enzyme is a potential therapeutic target for beta(0)-thalassernia/HbE patients.
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