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EDITORIALS
Novel use for selective inhibitors of nuclear export in β-thalassemia: block of HSP70 export from the nucleus via exportin Xpo1 improves ineffective erythropoiesis
Susree Modepalli1 and Shilpa M. Hattangadi2
1Georgetown University School of Medicine, Washington DC and 2National Institutes of Health, Bethesda, MD, USA E-mail: SHILPA M. HATTANGADI - shilpam.hattangadi@nih.gov
doi:10.3324/haematol.2020.254474
Thalassemia is the most prevalent monogenic recessive members of the transforming growth factor-beta (TGF-β) fam-
hereditary blood disorder, with around 300,000 chil- ily and Activin receptor-II (ActR-II) trap ligands that stimulate 12
dren affected at birth worldwide. Imbalance between a- and non-a-globin chains results in premature death of dif- ferentiating 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 erythro- poiesis, 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
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 cur- rent issue of Haematologica, Guillem et al.3 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
Figure 1. KPT-251 inhibition of HSP70 export from the nucleus via exportin Xpo1 improves ineffective erythropoiesis in β-thalassemia. Under normal conditions, nuclear HSP70 protects GATA1 from caspase-3 cleavage. In thalassemia, excess free a-globin chains sequester HSP70 in the cytoplasm, prevent normal GATA1 target expression, and result in ineffective erythropoiesis. Treating erythroblasts with the Xpo1 inhibitor KPT-251 increases nuclear levels of HSP70, rescues GATA1 from caspase-3 cleavage, and improves terminal erythroid development.
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haematologica | 2020; 105(9)