Konference: 2015 57th ASH Annual Meeting - účast ČR
Kategorie: Maligní lymfomy a leukémie
Téma: 112. Thalassemia and Globin Gene Regulation: Poster III
Číslo abstraktu: 3373
So far, 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 known as th3/th3. Our data indicates that HO-1 expression is increased in the liver, spleen and kidney of β-thalassemic mice compared to wild-type mice. Importantly, we observed that erythropoietin-mediated erythroid differentiation of fetal liver (FL) cells isolated from β-thalassemic fetuses have increased levels of HO-1 at mRNA and protein levels as well as a decrease in phosphorylated eIF2-α levels. Ferritin levels were increased in β-thalassemic FL cells suggesting increased heme catabolism and iron release. To investigate the contribution of HO-1 to the pathology associated with β-thalassemia, wild-type and thalassemic (th3/+) mice were injected with 40 µmoles/kg/d of tin-protoporphyrin IX (SnPP, HO-1 inhibitor) during a 4-week period, 3 times a week. Our results show that β-thalassemic mice injected with SnPP display a decrease in the spleen index, hemoglobin levels, red blood cell counts, reticulocyte counts and liver iron content when compared to PBS injected β-thalassemic mice. Additionally, HO-1 inhibition reduced ineffective erytropoiesis in β-thalassemia mice. Our results indicate that β-thalassemic erythroblasts have inappropriately high levels of “free” heme that is continuously degraded by HO-1. Further research is needed to determine whether iron liberated from heme by HO-1 is directly 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.
Datum přednesení příspěvku: 7. 12. 2015