Pathogenesis and Therapy of a New Model of SOD2 Deficiency-Induced Sideroblastic Anemia.

Manganese superoxide dismutase (SOD2) is a major antioxidant protein which protects cells against the toxicity of superoxide anion, a by-product of mitochondrial respiration. While knockout of SOD2 results in late embryonic or early neonatal death, SOD2 deficient hematopoeitic stem cells (HSC) are capable of rescuing lethally irradiated normal hosts. The resulting hematopoeitic chimeric mice show a persistent hemolytic anemia similar to human sideroblastic anemia. Loss of SOD2 in erythroid progenitor cells results in mitochondrial proliferation and excess iron deposition within mitochondria of reticulocytes. Mature red blood cell (RBC) show abundant iron inclusions with evidence of a defect in iron incorporation into heme and altered survival. SOD2 deficient cells show both enhanced reactive oxygen species production and protein oxidative damage. We recently published a comparative RBC proteome analysis. Our results show that the expression of several proteins involved in folding/chaperone function, redox regulation, ATP synthesis and RBC metabolism is altered in SOD2 deficient cells. To define early events in the pathogenesis, we are currently performing a gene expression array strategy. The overall goal of this procedure is to characterize differential gene expression at the level of TER-119⁺ CD71⁺ erythroid precursor cells from the bone marrow of SOD2 deficient HSC mice versus wild-type and antioxidant-treated SOD2 deficient recipients. Preliminary analysis generated a list of 718 genes as significantly discriminating between wild-type and SOD2 deficient RBC progenitors. Taken together, our results and subsequent validation of candidate genes in in vivo experiments will identify genes involved in response of erythroid progenitors to oxidative stress as well as determinants of RBC lifespan in other hemolytic disorders.