Thalassemias are a heterogeneous group of red blood cell disorders ranging from a clinically severe phenotype requiring life-saving transfusions (thalassemia major) to a relatively moderate symptomatic disorder, sometimes requiring transfusions (thalassemia intermedia). Thalassemia minor, the least severe form of the disorder, is characterized by minimal to mild symptoms. While thalassemia minor and intermedia are vastly more prevalent than thalassemia major, the latter is often fatal when not treated. Though considered a major cause of morbidity and mortality worldwide, there is still no universally available cure for this severe form of thalassemia. A reason for this is at least in part due to the lack of full understanding of pathophsyiology of thalassemia. The underlying cause of pathology in thalassemia is the premature apoptotic destruction of erythroblasts causing ineffective erythropoeisis. Normally, the assembly of adult hemoglobin (consisting of a tetramer of two α- and two β-globin chains) features a very tight coordination of α- and β-globin chain synthesis. However, in β-thalassemia, β-globin synthesis is decelerated causing α-globin accumulation; while in α-thalassemia the opposite scenario occurs. Unpaired globin chains that accumulate in thalassemic erythroblasts are bound to heme. In addition, in β-thalassemia an erythroid specific protease destroys excess α-globin chains, likely leading to the generation of a pool of “free” heme in erythroblasts. “Free” heme is toxic, but this toxicity will likely be augmented, if heme oxygenase 1 (HO-1) can release iron from heme. To date, virtually no information about the expression of HO-1 in erythroblasts has been produced; however, we have recently provided unequivocal evidence that this enzyme is present in several model erythroid cells1. Based on this novel and important finding, we hypothesize that in β-thalassemic erythroblasts HO-1 mediated release of iron from heme is the major culprit responsible for cellular damage. To test this hypothesis we exploited the mouse model of β-thalassemia, th3/th3. Thus far, our data indicates that HO-1 expression is increased in liver, spleen and kidney of β-thalassemic mice compared to wild type mice. Importantly, we observed that Epo-mediated erythroid differentiation of fetal liver (FL) cells isolated from β-thalassemic fetuses, display increased levels of HO-1 at mRNA and protein levels as well as decreased phosphorylated eiF2-α. Ferritin levels are also increased in these cells suggesting increased heme catabolism and iron release. Altogether, these results indicate that β-thalassemic erythroblasts have inappropriately high levels of unbound heme that is continuously degraded by HO-1. Further research is needed to determine whether HO-1 liberated iron is responsible for the damage of β-thalassemic erythroblasts.
1Garcia-Santos D, et al. Heme oxygenase 1 is expressed in murine erythroid cells where it controls the level of regulatory heme. Blood 123 (14): 2269-77, 2014.
No relevant conflicts of interest to declare.
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