Molecular Pathology Laboratory, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand.
Blood Cells Mol Dis. 2011 Oct 15;47(3):143-57. doi: 10.1016/j.bcmd.2011.06.005. Epub 2011 Jul 23.
Erythropoiesis in β0-thalassaemia/Hb E patients, the most common variant form of β-thalassaemia in Southeast Asia, is characterized by accelerated differentiation and over-expansion of erythroid precursor cells. The mechanism driving this accelerated expansion and differentiation remain unknown. To address this issue a proteomic analysis was undertaken to firstly identify proteins differentially expressed during erythroblast differentiation and a second analysis was undertaken to identify proteins differentially expressed between β0-thalassaemia/Hb E erythroblasts and control erythroblasts. The majority of proteins identified as being differentially expressed between β0-thalassaemia/Hb E and control erythroblasts were constituents of the glycolysis/TCA pathway and levels of oxidative stress correlated with the degree of erythroid expansion. A model was constructed linking these observations with previous studies showing increased phosphorylation of ERK1/2 in thalassemic erythroblasts which predicted the increased activation of PKA, PKB and PKC which Western analysis confirmed. Inhibition of PKA or PKC reduced β0-thalassaemia/Hb E erythroblast differentiation and/or expansion. We propose that increased expansion and differentiation of β0-thalassaemia/Hb E erythroblasts occur as a result of feedback loops acting through increased oxidative metabolism.
β0-地中海贫血/血红蛋白 E（HbE）病是东南亚地区最常见的β-地中海贫血变异形式，其特征为红系前体细胞的加速分化和过度扩张。导致这种加速扩张和分化的机制尚不清楚。为了解决这个问题，进行了蛋白质组学分析，首先鉴定了在红系母细胞分化过程中差异表达的蛋白，其次鉴定了β0-地中海贫血/HbE 红系母细胞和对照红系母细胞之间差异表达的蛋白。在β0-地中海贫血/HbE 和对照红系母细胞之间差异表达的大多数蛋白是糖酵解/TCA 途径的组成部分，氧化应激水平与红系扩张程度相关。构建了一个模型，将这些观察结果与先前的研究联系起来，先前的研究表明，地中海贫血红系母细胞中 ERK1/2 的磷酸化增加，这预示着 PKA、PKB 和 PKC 的激活增加，Western 分析证实了这一点。PKA 或 PKC 的抑制减少了β0-地中海贫血/HbE 红系母细胞的分化和/或扩张。我们提出，β0-地中海贫血/HbE 红系母细胞的过度扩张和分化是由于通过增加氧化代谢起作用的反馈环所致。
