Novel use for selective inhibitors of nuclear export in β-thalassemia: block of HSP70 export from the nucleus via exportin Xpo1 improves ineffective erythropoiesis

Thalassemia is the most prevalent monogenic recessive hereditary blood disorder, with around 300,000 children affected at birth worldwide. Imbalance between aand non-a-globin chains results in premature death of differentiating erythroid precursors (erythroblasts), because as a-globin tetramers accumulate and precipitate, they form inclusion bodies that cause oxidative membrane damage and destruction by apoptosis. Premature death of differentiating erythroblasts that are dividing faster because of anemia is termed ineffective erythropoiesis, as increased precursors still results in fewer terminal erythrocytes. The hypoxic environment created by anemia leads to increases in factors such as erythropoietin (Epo) or members of the transforming growth factor-beta (TGF-β) family and Activin receptor-II (ActR-II) trap ligands that stimulate erythropoiesis that continues to be ineffective. Continued apoptosis of abnormal precursors results in hemolytic anemia, aggravating other major complications of the disease like iron overload that stem from ineffective erythropoiesis. In the current issue of Haematologica, Guillem et al. present a novel potential therapeutic strategy for β-thalassemia, by mitigating the deleterious effect of excess a-globin chains through increased nuclear density of chaperone HSP70 by inhibiting its nuclear export. Multiple novel treatment modalities have been shown to ameliorate symptoms of thalassemia. These are directed either