Cao Hua, Jung Manfred, Stamatoyannopoulos George
Division of Medical Genetics, University of Washington, Seattle, 98195, USA.
Exp Hematol. 2005 Dec;33(12):1443-9. doi: 10.1016/j.exphem.2005.08.007.
The hydroxamic acid derivatives of short-chain fatty acids, butyryl and propionyl hydroxamate, subericbishydoxamic acid, and suberoylanilide hydroxamic acid, are potent inhibitors of histone deacetylase (HDAC) and have been shown to induce fetal hemoglobin in vitro. In this study we examined whether these compounds have erythropoietic activity and can induce gamma globin gene expression in vivo.
Transgenic mice heterozygous for a deletion beta thalassemia and hemizygous for a human gamma globin transgene were treated with these compounds and hematologic responses as well as the induction of gamma gene expression were evaluated. Hematologic studies included measurement of reticulocytes, hematocrit, and the in vivo levels of BFU-E. Effects on globin gene expression were assessed by measuring F reticulocytes and the human gamma/murine alpha globin mRNA ratios by RNAse protection assay.
Propionyl and butyryl hydroxamate increased reticulocytes by 71% and 139%, the in vivo BFU-E counts by 75% and 51%, and the in vivo gamma gene expression by 33.9% and 71% respectively. SBHA and SAHA had no erythropoietic activity in vivo.
Hydroxamic acid derivatives can stimulate the in vivo erythropoiesis and fetal globin production in a thalassemic murine model. The combined effect of certain histone deacetylase inhibitors on erythropoiesis and on gamma gene expression make these compounds desirable targets for development of therapeutics for beta chain hemoglobinopathies.
短链脂肪酸的异羟肟酸衍生物，如丁酰异羟肟酸、丙酰异羟肟酸、辛二酰双异羟肟酸和伏立诺他，是组蛋白脱乙酰酶（HDAC）的有效抑制剂，且已证实在体外可诱导胎儿血红蛋白生成。在本研究中，我们检测了这些化合物是否具有促红细胞生成活性以及能否在体内诱导γ珠蛋白基因表达。
对缺失β地中海贫血杂合子和人γ珠蛋白转基因半合子的转基因小鼠用这些化合物进行处理，并评估血液学反应以及γ基因表达的诱导情况。血液学研究包括网织红细胞计数、血细胞比容测定以及体内爆式红系集落形成单位（BFU-E）水平的检测。通过核糖核酸酶保护试验测量F网织红细胞以及人γ/鼠α珠蛋白mRNA比值，评估对珠蛋白基因表达的影响。
丙酰异羟肟酸和丁酰异羟肟酸分别使网织红细胞增加71%和139%，体内BFU-E计数增加75%和51%，体内γ基因表达分别增加33.9%和71%。辛二酰双异羟肟酸（SBHA）和伏立诺他（SAHA）在体内无促红细胞生成活性。
异羟肟酸衍生物可刺激地中海贫血小鼠模型体内的红细胞生成和胎儿珠蛋白生成。某些组蛋白脱乙酰酶抑制剂对红细胞生成和γ基因表达的联合作用使这些化合物成为β链血红蛋白病治疗药物开发的理想靶点。
