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• W2584049216 abstract "Abstract The DNA methyltransferase (DNMT) inhibitor decitabine increases fetal hemoglobin (HbF) in experimental primates and to therapeutic levels in patients with sickle cell disease. Decitabine-DNMT covalent adducts formed following incorporation of decitabine into newly synthesized DNA can activate DNA damage/stress response signal transduction pathways. To test the hypothesis that DNA damage/stress response pathways are involved in the ability of decitabine to increase γ-globin expression, experiments were performed in a chemical inducer of dimerization (CID)-dependent mouse fetal bone marrow (BM)-derived cell line containing the human β-globin gene locus in the context of a yeast artificial chromosome and in primary baboon erythroid progenitors derived from CD34+ BM cells grown in Iscove’s media containing 30% fetal bovine serum, 2U/ml epo, 200ng/ml SCF, and 1uM dexamethasone. Addition of decitabine (1μM) to both the CID-dependent mouse BM cell line and erythroid progenitors on day 7 of culture increased phospho-H2A.X and phospho-p38 in Western blot assays demonstrating activation of the ATM/ATR and p38 MAP kinase signal transduction pathways. Decitabine increased γ-globin 280 fold and ε-globin 38 fold in the mouse BM cell line as determined by real time PCR using the ΔΔCT method with mouse α-globin as the standard. Co-addition of the p38 MAP kinase inhibitor SB203580 reduced γ-globin induction 93.4% and ε-globin induction 88.4% in the mouse BM cell line. In primary erythroid progenitors, decitabine increased γ-globin 2.8 fold and ε-globin 44 fold. SB203580 reduced decitabine-mediated ε-globin induction 46% while no significant effect on the level of γ-globin induction was observed. Decitabine also increased phospho-CREB in the mouse BM cell line, a target of the p38 MAP kinase pathway required for γ-globin induction by histone deacetylase inhibitors. These results suggest that activation of the p38 MAP kinase pathway is required for induction of ε- and γ-globin expression by decitabine in the mouse fetal BM cell line and may contribute to increased ε-globin expression in primary erythroid progenitors. Additional Western blot analysis showed that decitabine treatment of erythroid progenitors increased p21WAF1 and p27KIP1 48–72 hours following addition of drug. Examination of Wright’s stained cytospin preparations from decitabine-treated cultured erythroid progenitors showed that orthochromatic erythroblasts were increased &gt;2 fold and basophilic erythroblasts were decreased 5 fold compared to untreated controls 96–120 hours post-drug addition at doses ranging from 0.125 to 1.0mM. These results demonstrate that decitabine increases terminal erythroid differentiation within this cell population. As RB protein is required for cell cycle exit and terminal erythroid differentiation, we suggest that induction of terminal differentiation by decitabine is mediated by the effect of increased p21WAF1 and p27KIP1 on RB phosphorylation. Because of the known asynchrony of γ- and β-globin expression during erythroid differentiation, the ability of decitabine to induce terminal erythroid differentiation could play a role in its ability to increase γ-globin expression. We conclude that activation of DNA damage/stress response pathways by decitabine may contribute to its ability to increase γ-globin expression and induce terminal erythroid differentiation." @default.
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• W2584049216 date "2008-11-16" @default.
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• W2584049216 title "The Role of DNA Damage/Stress Response Pathways in the Mechanism of Action of Decitabine" @default.
• W2584049216 doi "https://doi.org/10.1182/blood.v112.11.490.490" @default.
• W2584049216 hasPublicationYear "2008" @default.
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