Published online 16 July 2009
Haematologica, Vol 94, Issue 9, 1211-1219 doi:10.3324/haematol.2009.005827
Copyright © 2009 by Ferrata Storti Foundation
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Thalassemia Sydromes

Imbalanced globin chain synthesis determines erythroid cell pathology in thalassemic mice

Kanitta Srinoun1,2, Saovaros Svasti1,3, Worrakavee Chumworathayee1,4, Jim Vadolas5, Phantip Vattanaviboon2, Suthat Fucharoen1, Pranee Winichagoon1

1 Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakornpathom, Thailand
2 Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand
3 Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
4 Interdisciplinary Graduate Program in Genetic I Engineering, Kasetsart University, Bangkok, Thailand
5 CAGT Research Group, The Murdoch Children’s Research Institute, Royal Children’s Hospital, Victoria, Australia

Correspondence: Pranee Winichagoon Fucharoen, PhD, Thalassemia Research Center, Institute of Science and Technology for Research and Development, Mahidol University, Salaya, Phuttamonthon 4 Rd. Phuttamonthon, Nakornpathom 73170 Thailand. E-mail:stpfc{at}mahidol.ac.th

Background: β-thalassemia occurs from the imbalanced globin chain synthesis due to the absence or inadequate β-globin chain production. The excessive unbound {alpha}-globin chains precipitate in erythroid precursors and mature red blood cells leading to ineffective erythropoiesis and hemolysis.

Design and Methods: In vitro globin chain synthesis in reticulocytes from different types of thalassemic mice was performed. The effect of imbalanced globin chain synthesis was assessed from changes of red blood cell properties including increased numbers of red blood cells vesicles and apoptotic red blood cells, increased reactive oxygen species and decreased red blood cell survival.

Results: The {alpha}/β-globin chain ratio in βIVSII-654-thalassemic mice, 1.26±0.03, was significantly higher than that of wild type mice, 0.96±0.05. The thalassemic mice show abnormal hematologic data and defective red blood cell properties. These values were improved significantly in doubly heterozygous thalassemic mice harboring 4 copies of human βE-globin transgene, with a more balanced globin chain synthesis, 0.92±0.05. Moreover, transgenic mice harboring 8 extra copies of the human βE-globin transgene showed inversely imbalanced {alpha}/β-globin synthesis ratio, 0.83±0.01, that resulted in a mild β-thalassemia phenotype due to the excessive β-globin chains. The degree of ineffective erythropoiesis also correlated with the degree of imbalanced globin chain synthesis. Bone marrow and splenic erythroid precursor cells of βIVSII-654-thalassemic mice showed increased phosphatidylserine exposure in basophilic and polychromatophilic stages, which was restored to the normal level in doubly heterozygous mice.

Conclusions: Imbalanced {alpha}/β-globin chain as a consequence of either reduction or enhancement of β-globin chain synthesis can cause abnormal red blood cell properties in mouse models.

Key words: thalassemia, transgenic mice, ineffective erythropoiesis, globin chain synthesis.