Differences in response to fetal hemoglobin induction therapy in β-thalassemia and sickle cell disease
Differences in response to fetal hemoglobin induction therapy in β-thalassemia and sickle cell disease
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DOI：
10.1016/j.bcmd.2009.02.006
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发表时间：
2009-07-01
影响因子：
2.3
通讯作者：
Atweh, George F.
中科院分区：
文献类型：
--
作者：
Fathallah, Hassana;Taher, Ali;Atweh, George F.
胎儿血红蛋白（HbF）诱导剂在镰状细胞病（SCD）的治疗中显示出相当大的前景。然而，相同的药剂在β-地中海贫血（β-Thal）中显示出较少的临床活性。为了了解这些临床疗效差异的基础，我们比较了丁酸盐和氯化血红素对中间型β-Thal和SCD患者的祖细胞衍生红系细胞中不同珠蛋白基因表达的影响。暴露于丁酸盐导致SCD和β-Thal中γ-珠蛋白mRNA水平的增加。有趣的是，丁酸盐暴露增加β-Thal中α-珠蛋白的表达，而SCD中α-珠蛋白mRNA水平响应于丁酸盐而降低。结果，丁酸盐诱导的γ-珠蛋白表达增加对β-Thal中α：β样珠蛋白mRNA失衡的有利影响由于α-珠蛋白表达的相关增加而降低。氯化血红素对这两类患者的所有三种珠蛋白基因有相似但不太深刻的影响。虽然大多数β-Thal患者没有纠正他们的球蛋白失衡，以响应丁酸盐或氯化血红素诱导的HbF，但少数患者的球蛋白失衡显著减少。因此，我们认为大多数β-Thal患者对γ-珠蛋白表达诱导剂的临床反应较差可能反映了这些药物对其他珠蛋白基因的不利影响。(C)2009 Elsevier Inc. All rights reserved.
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.