3072 - Intrinsic Pathophysiological Features of Erythroid Cells Derived From Various Thalassemia Syndromes

Abstract

Ineffective erythropoiesis including increased cell expansion, limited differentiation, and premature death of erythroid precursors contribute to pathology of thalassemia syndromes. Previous studies mostly focus in the erythropoiesis of -thalassemia major whilst scanty explored among other thalassemia diseases. In this study, we investigated thalassemic erythroid cell features that could lead to its pathophysiology including proliferation rate, maturation ability, apoptosis and hemoglobin quantity by using ex vivo culture of CD34+ hematopoietic progenitor cells derived from patients with common thalassemias in Southeast Asia including homozygous -thalassemia, -thalassemia/HbE, HbH, and HbH-CS diseases. As expected, the poorest capability to produce hemoglobin was observed in homozygous -thalassemia erythroids. We found an accelerated expansion but limited terminal erythroid differentiation in all type of thalassemia erythroid cells, but the extremely delayed maturation was presented in homozygous -thalassemia cells. Notably, erythroid cell death was distinctly appeared only in homozygous -thalassemia corresponding with the down-regulation of anti-apoptotic Bcl-xL gene expression. Furthermore, we performed ex vivo culture of cells derived from -thalassemia/HbE patients presenting different degree of clinical severity; mildly-, moderately- and severely-affected. Interestingly, the erythroblasts derived from mildly-affected patients showed highest proliferation rate whereas the erythroblasts derived from severely-affected patients displayed extremely delay terminal erythroid maturation. This finding suggested that the degree of erythroid expansion and maturation arrest may contribute to the severity of -thalassemia/HbE patients. Altogether the results indicate that accelerated expansion but delay maturation together with failure hemoglobin production of erythroid cells are correlated with an exacerbation of ineffective erythropoiesis in both—and -thalassemias. Thus, a restores erythroid maturation could serve as a promising targeted therapies for thalassemias.