Journal
BLOOD CELLS MOLECULES AND DISEASES
Volume 47, Issue 3, Pages 143-157Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bcmd.2011.06.005
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Funding
- National Science and Technology Development Agency (NSTDA)
- Mahidol University
- Office of the Higher Education Commission
- Thai Royal Golden Jubilee Research Scholarship
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Erythropoiesis in beta(0)-thalassaemia/Hb E patients, the most common variant form of p-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 beta(0)-thalassaemia/Hb E erythroblasts and control erythroblasts. The majority of proteins identified as being differentially expressed between beta(0-)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 beta(0-)thalassaemia/Hb E erythroblast differentiation and/or expansion. We propose that increased expansion and differentiation of beta(0)-thalassaemia/Hb E erythroblasts occur as a result of feedback loops acting through increased oxidative metabolism. (C) 2011 Elsevier Inc. All rights reserved.
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