Thalidomide induces γ-globin gene expression through increased reactive oxygen species–mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis
- 15 October 2007
- journal article
- Published by American Society of Hematology in Blood
- Vol. 110 (8), 2864-2871
- https://doi.org/10.1182/blood-2007-01-065201
Abstract
Although thalidomide has been shown to improve anemia in some patients with myelodysplastic syndromes and stimulates erythropoietin in patients with multiple myeloma, thalidomide's specific effects on γ-globin gene expression during erythroid differentiation have not been studied. Here, we investigated the effects of thalidomide on γ-globin gene expression and the involved signaling pathway using an ex vivo culture system of primary human CD34+ cells. We found that thalidomide induced γ-globin mRNA expression in a dose-dependent manner, but had no effect on β-globin expression. We also demonstrated that intracellular reactive oxygen species (ROS) levels were increased by treatment with thalidomide for 48 hours (from day 3 to day 5). Western blot analysis demonstrated that thalidomide activated the p38 mitogen-activated protein kinase (MAPK) signaling pathway in a time- and dose-dependent manner and increased histone H4 acetylation. Pretreatment of cells with the antioxidant enzyme catalase and the intracellular hydroxyl scavenger dimethylthiourea (DMTU) abrogated the thalidomide-induced p38 MAPK activation and histone H4 acetylation. Moreover, pretreatment with catalase and DMTU diminished thalidomide-induced γ-globin gene expression. These data indicate that thalidomide induces increased expression of the γ-globin gene via ROS-dependent activation of the p38 MAPK signaling pathway and histone H4 acetylation.Keywords
This publication has 47 references indexed in Scilit:
- Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves γ-globin activation by CREB1 and ATF-2Blood, 2006
- Short-chain fatty acids induce γ-globin gene expression by displacement of a HDAC3-NCoR repressor complexBlood, 2006
- Fetal hemoglobin induction by histone deacetylase inhibitors involves generation of reactive oxygen speciesExperimental Hematology, 2006
- Reactive oxygen species generated by hematopoietic cytokines play roles in activation of receptor-mediated signaling and in cell cycle progressionCellular Signalling, 2006
- Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesisBlood, 2005
- Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidinBlood, 2003
- Hypothesis: Thalidomide embryopathy?proposed mechanism of actionTeratology, 2000
- Thalidomide Inhibits Angiogenesis in Embryoid Bodies by the Generation of Hydroxyl RadicalsThe American Journal of Pathology, 2000
- Antitumor Activity of Thalidomide in Refractory Multiple MyelomaThe New England Journal of Medicine, 1999
- Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell AnemiaThe New England Journal of Medicine, 1995