Journal
BLOOD CELLS MOLECULES AND DISEASES
Volume 43, Issue 1, Pages 58-62Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bcmd.2009.02.006
Keywords
Thalassemia; Sickle cells; Hemoglobin expression; Butyrate; Hemin
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Funding
- National Institutes of Health [HL-073438]
- Ovation Pharmaceuticals
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Inducers of fetal hemoglobin (HbF) have shown considerable promise in the treatment of sickle cell disease (SCD). However, the same agents have shown less clinical activity in beta-thalassemia (beta-Thal). To understand the basis of these differences in clinical effectiveness, we compared the effects of butyrate and hemin on the expression of the different globin genes in progenitors-derived erythroid cells from patients with beta-Thal intermedia and SCD. Exposure to butyrate resulted in an augmentation of gamma-globin mRNA levels in both SCD and beta-Thal. Interestingly, butyrate exposure increased alpha-globin expression in beta-Thal, while alpha-globin mRNA levels decreased in SCD in response to butyrate. As a result, the favorable effects of the butyrate-induced increase in gamma-globin expression on alpha:beta-like globin mRNA imbalance in beta-Thal were reduced as a result of the associated increase in alpha-globin expression. Hemin had similar but less profound effects on all three globin genes in both categories of patients. Although the majority of patients with beta-Thal did not correct their globin imbalance in response to butyrate or hemin induction of HbF in a minority of patients resulted in marked reduction in globin imbalance. Thus, we believe that the poor clinical response in a majority of patients with beta-Thal to inducers of gamma-globin expression may be a reflection of unfavorable effects of these agents on the other globin genes. (C) 2009 Elsevier Inc. All rights reserved.
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