Hydroxamide derivatives of short-chain fatty acid have erythropoietic activity and induce gamma gene expression in vivo.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Cao
Hua
H
Division of Medical Genetics, University of Washington, Seattle, 98195, USA. huacao@u.washington.edu
Jung
Manfred
M
Stamatoyannopoulos
George
G
D000818:Animals; D004195:Disease Models, Animal; D015672:Erythroid Precursor Cells / Q000166:cytology; D004920:Erythropoiesis / Q000187:drug effects*; D005232:Fatty Acids, Volatile / Q000737:chemistry / Q000494:pharmacology*; D005319:Fetal Hemoglobin / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005914:Globins / Q000235:genetics*; D006453:Hemoglobinopathies / Q000188:drug therapy; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D051379:Mice; D008822:Mice, Transgenic; D017701:Reticulocyte Count; D013329:Structure-Activity Relationship; D017086:beta-Thalassemia / Q000235:genetics
D005232:Fatty Acids, Volatile; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D005914:Globins; D005319:Fetal Hemoglobin