Hemoglobin switching in unicellular erythroid culture of sibling erythroid burst-forming units: kit ligand induces a dose-dependent fetal hemoglobin reactivation potentiated by sodium butyrate

作     者：Gabbianelli, M Testa, U Massa, A Pelosi, E Sposi, NM Riccioni, R Luchetti, L Peschle, C 

作者机构：Thomas Jefferson Univ Kimmel Canc Ctr Philadelphia PA 19107 USA Ist Super Sanita Dept Hematol & Oncol I-00161 Rome Italy 

出 版 物：《BLOOD》 (血液)

年 卷 期：2000年第95卷第11期

页      面：3555-3561页

核心收录：

学科分类：1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

主　　题：丁酸盐类/药理学 细胞培养技术/方法 细胞分化/药物作用 细胞 培养的 红细胞/细胞学 红细胞/药物作用 红细胞/生理学 红细胞生成素 重组/药理学 胎儿血红蛋白/生物合成 基因 开关 珠蛋白类/生物合成 粒细胞巨噬细胞集落刺激因子/药理学 造血干细胞/细胞学 造血干细胞/药物作用 造血干细胞/生理学 血红蛋白A/生物合成 白细胞介素3/药理学 重组蛋白质类/药理学 干细胞因子/药理学 成年人 人类 男(雄)性 

摘      要：Mechanisms underlying fetal hemoglobin (HbF) reactivation In adult life have not been elucidated;particularly, the role of growth factors (GFs) is controversial. Interestingly, histone deacetylase (HD) inhibitors (sodium butyrate, NaB, trichostatin A, TSA) reactivate HbF. We developed a novel model system to investigate HbF reactivation: (1) single hematopoietic progenitor cells (HPCs) were seeded in serum-free unilineage erythroid culture;(2) the 4 daughter cells (erythroid burst-forming units, [BFU-Es]), endowed with equivalent proliferation/differentiation and HbF synthesis potential, were seeded in 4 unicellular erythroid cultures differentially treated with graded dosages of GFs and/or HD inhibitors;and (3) HbF levels were evaluated in terminal erythroblasts by assay of F cells and gamma-globin content (control levels, 2.4% and 1,8%, respectively, were close to physiologic values). HbF was moderately enhanced by interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor treatment (up to 5%-8% gamma-globin content), while sharply reactivated in a dose-dependent fashion by c-kit ligand (KL) and NaB (20%-23%). The stimulatory effects of KL on HbF production and erythroid cell proliferation were strictly correlated. A striking increase of HbF was induced by combined addition of KL and NaB or TSA (40%-43%), This positive interaction is seemingly mediated via different mechanisms: NaB and TSA may modify the chromatin structure of the beta-globin gene cluster;KL may activate the gamma-globin promoter via up-modulation of tal-1 and possibly FLKF transcription factors. These studies indicate that KL plays a key role in HbF reactivation in adult life, furthermore, combined KL and NaB administration may be considered for sickle cell anemia and beta-thalassemia therapy. (Blood. 2000;95:3555-3561) (C) 2000 by The American Society of Hematology.