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Enhanced activation of autophagy in β-thalassemia/Hb E erythroblasts during erythropoiesis

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Abstract

Erythropoiesis in β-thalassemia patients is ineffective, primarily because of death of the erythroid progenitor cells at the polychromatic normoblast stage. While it is known that autophagy plays a critical role during erythropoiesis by removing organelles from erythroid cells during terminal differentiation, its role in erythroid cells whose function is impaired remains to be explored. To investigate this, CD34+ erythroid progenitor cells from normal controls and β-thalassemia/Hb E patients were isolated from peripheral blood and cultured under conditions driving differentiation into an erythroid lineage, and levels of autophagy and apoptosis were analyzed both directly and after biochemical manipulation with l-asparagine. A significantly higher level of autophagy was seen in β-thalassemia/Hb E erythroblasts as compared to normal control erythroblasts during erythropoiesis. Interestingly, this activation was mediated in part by the presence of high levels of Ca2+ as modulation of Ca2+ levels significantly reduced the level of autophagy in these cells. Inhibition of autophagic flux in normal erythroblasts significantly increased apoptosis in normal erythroblasts, but not in thalassemic erythroblasts, although sensitivity to autophagic flux inhibition was restored by reduction of Ca2+ levels. These results suggest that high levels of autophagy in β-thalassemia/HbE erythroblasts may contribute to the increased levels of apoptosis that lead to ineffective erythropoiesis in β-thalassemia/Hb E erythroblasts.

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Acknowledgments

This work was supported by a Research Strengthening Grant from the National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Development Agency (NSTDA) and Mahidol University. P.L. is supported by a Thai Royal Golden Jubilee Research Ph.D. Scholarship, A.L. is supported by the Thai Commission on Higher Education Ph.D. Scholarship, and T.W was supported by a BIOTEC Ph.D. Scholarship.

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Authors and Affiliations

  1. Molecular Pathology Laboratory, Institute of Molecular Biosciences, Mahidol University, Salaya Campus, 25/25 Phuttamonthon Sai 4, Salaya, Nakon Pathom, Thailand, 73170

    Pathrapol Lithanatudom, Tirawat Wannatung, Amporn Leecharoenkiat & Duncan R. Smith

  2. Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Salaya, Thailand

    Saovaros Svasti & Suthat Fucharoen

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  1. Pathrapol Lithanatudom
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  2. Tirawat Wannatung
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  3. Amporn Leecharoenkiat
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  4. Saovaros Svasti
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  5. Suthat Fucharoen
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  6. Duncan R. Smith
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Correspondence to Duncan R. Smith.

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Lithanatudom, P., Wannatung, T., Leecharoenkiat, A. et al. Enhanced activation of autophagy in β-thalassemia/Hb E erythroblasts during erythropoiesis. Ann Hematol 90, 747–758 (2011). https://doi.org/10.1007/s00277-010-1152-5

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  • DOI: https://doi.org/10.1007/s00277-010-1152-5

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