Accelerated programmed cell death (apoptosis) in erythroid precursors of patients with severe beta-thalassemia (Cooley's anemia) [see comments]

Abstract

The profound and life-threatening anemia in patients with Cooley's anemia is ascribed primarily to intramedullary hemolysis (ineffective erythropoiesis), the cause of which is obscure. Based on prior morphologic data showing nuclear abnormalities, we hypothesized that accelerated apoptosis could occur in these erythroid precursors. The highly successful bone marrow (BM) transplantation program for patients with Cooley's anemia provided us with a unique opportunity to test this hypothesis. We obtained pretransplantation BM aspiration samples from patients undergoing BM transplantation in Pesaro, Italy and from their allogeneic donors. The erythroid precursors were isolated using ficoll sedimentation and then panning selecting fro CD45- cells. Cytospin and Giemsa staining showed that the separation provided greater than 90% erythroblasts. Five million of these erythroblasts were lysed and their DNA was isolated. There were obvious ladder patterns of DNA breakdown products in beta-thalassemia major samples, with less occurring in beta- thalassemia trait. Normal individuals showed only a slight smear of breakdown of DNA. These results indicate there is enhanced apoptosis in the erythroblasts in the BMs of Cooley's anemia patients. This finding might partially explain why most of these erythroblasts never survive to become mature erythrocytes.

Rescued Mice with Hb E Transgene‐Developed Red Cell Changes Similar to Human β‐Thalassemia/HbE Disease

“…14 Previous studies revealed that RBCs that underwent apoptosis expressed the PS to the outer leaflet of the membrane. 15 The β-knockout mice, which have already been characterized as having thalassemia intermedia, expressed the increased extramedullary hematopoiesis, severe anemia, and high rate of RBC turnover as observed from the reticulocyte count and indirect bilirubin. 10 Few studies in the other β-thalassemic model (Hbb th-1 ), which also has a phenotype similar to that of human β-thalassemia intermedia, demonstrated that the murine β-globin chains could bind to the red cell membrane skeleton, as in humans, and the amount of α-globin bound correlated strongly with the membrane rigidity and severity of anemia.…”

Induction of Fetal Globin in β‐Thalassemia: Cellular Obstacles and Molecular Progress

“…The β-thalassemia syndromes are characterized by deficiency of β-globin chains and excess α-globin, with consequent red cell membrane damage and rapid apoptosis of early erythroblasts developing in the bone marrow. [1][2][3][4][5][6][7][8] It is well established that continued high expression of fetal globin results in less severe anemia and milder clinical courses. [1][2][3][4] From analysis of globin chain ratios of thalassemia trait and thalassemia intermedia subjects, non-α (fetal and β) globin chains that balance αglobin by approximately 50% result in transfusion independence and milder clinical courses.…”

“…1,2,5 Rapid cellular apoptosis is well characterized in β-thalassemia from the precipitation of α-globin chains. [6][7][8] Optimal hematologic correction of β-thalassemia may require improvement in the underlying erythroid cell survival or proliferation to allow an agent that induces fetal globin expression to act before the programmed cell death pathway is irrevocably established. Chemotherapeutic agents that stimulate fetal globin production, such as 5-azacytidine, decitabine, and hydroxyurea, all inhibit cell proliferation and cause cell growth arrest, which is known to promote irreversible apoptosis in cancer cells.…”

Cellular and Molecular Effects of a Pulse Butyrate Regimen and New Inducers of Globin Gene Expression and Hematopoiesis

“…[1][2][3][4] The toxicity of unmatched α-globin chains results in early programmed cell death with intramedullary hemolysis of thalassemic erythroid progenitors. 5 Analyses of different globin gene mutations and clinical studies have demonstrated that increased expression of fetal globin can ameliorate the β-thalassemias, as γ-globin chains can balance the excess α globin and improve red blood cell survival. [1][2][3][4]6,7 However, a narrow window exists in which any γglobin stimulant must act before cell death occurs in thalassemia, making it difficult to reverse the cell destruction.…”