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The ineffective erythropoiesis observed in β-thalassemia is characterized by accelerated erythroid differentiation, maturation arrest and apoptosis at the polychromatophilic stage. During maturation of human β-thalassemia ery- throblasts, HSP70 is sequestrated in the cytoplasm (Figure 1) directly by excess free a-globin chains.14 GATA-1 is no longer protected, resulting in end-stage maturation arrest and apoptosis. Transduction of a nuclear-targeted HSP70 mutant or a caspase-3-uncleavable GATA-1 mutant restores terminal maturation of β-thalassemia erythroblasts.14 In this issue of Haematologica, Guillem et al.3 follow up on this mechanism to show that exportin-1 (XPO1) regulates the nucleocytoplasmic location of HSP70 in erythroid progeni- tors under normal conditions. Guillem et al. confirm that treating erythroblasts with the Xpo1 inhibitor KPT-251 increased nuclear levels of HSP70, rescued GATA1 from caspase-3 cleavage, and improved terminal erythroid devel- opment (Figure 1).
5. Lin MI, Paik E, Mishra B, et al. CRISPR/Cas9 genome editing to treat sickle cell disease and B-thalassemia: re-creating genetic variants to upregulate fetal hemoglobin appear well-tolerated, effective and durable. Blood. 2017;130(Supplement 1):284.
6. Shaeffer JR. Evidence for soluble alpha-chains as intermediates in hemoglobin synthesis in the rabbit reticulocyte. Biochem Biophys Res Comm. 1967;28(4):647-652.
7. Tavill AS, Grayzel AI, Vanderhoff GA, London IM. The control of hemoglobin synthesis. Trans Assoc Am Physicians. 1967;80:305- 313.
8. Olivieri NF, Weatherall DJ. Clinical aspects of beta thalassemia. In: Steinberg MH, Forget BG, Higgs DR, Nagel RL, eds. Disorders of Hemoglobin. Cambridge, United Kingdom: Cambridge University Press; 2001. pp. 277-341.
9. MorimotoR,FodorE.Cell-specificexpressionofheatshockproteins in chicken reticulocytes and lymphocytes. J Cell Biol. 1984;99 (4):1316-1323.
10. Singh MK, Yu J. Accumulation of a heat shock-like protein during differentiation of human erythroid cell line K562. Nature. 1984;309(5969):631-633.
11. Banerji SS, Laing K, Morimoto RI. Erythroid lineage-specific expres- sion and inducibility of the major heat shock protein HSP70 during avian embryogenesis. Genes Dev. 1987;1(9):946-953.
12. De Maria R, Zeuner A, Eramo A, et al. Negative regulation of ery- thropoiesis by caspase-mediated cleavage of GATA-1. Nature. 1999;401(6752):489-493.
13. Ribeil JA, Zermati Y, Vandekerckhove J, et al. Hsp70 regulates ery- thropoiesis by preventing caspase-3-mediated cleavage of GATA-1. Nature. 2007;445(7123):102-105.
14. Jean-Benoît A, Ribeil JA, Guillem F, et al. HSP70 sequestration by free a-globin promotes ineffective erythropoiesis in β-thalassaemia. Nature. 2014;514(7521):242-246.
15. Parikh K, Cang S, Sekhri A, Liu D. Selective inhibitors of nuclear export (SINE)–a novel class of anti-cancer agents. J Hematol Oncol. 2014;7:78.
16. Hing ZA, Fung HYJ, Ranganathan P, et al. Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hema- tological malignancies. Leukemia. 2016;30(12):2364-2372.
17. Gandhi UH, Senapedis W, Baloglu E, et al. Clinical implications of targeting XPO1-mediated nuclear export in multiple myeloma. Clin Lymphoma Myeloma Leuk. 2018;18(5):335-345.
Although the use of selective inhibitors of nuclear export (SINE) for the treatment of lymphomas and multi- ple myeloma has been well reported,15-17 this is the first
haematologica | 2020; 105(9)
2. Thein SL. Molecular basis of β thalassemia and potential therapeutic targets. Blood Cells Mos Dis. 2018;70:54-65.
3. Guillem F, Dussiot M, Colin E, et al. XPO1 regulates erythroid differ- entiation and is a new target for the treatment of β-thalassemia. Haematologica. 2020;105(9):2240-2249
4. Makis A, Hatzimichael E, Papassotiriou I, et al. 2017 Clinical trials update in new treatments of β‐thalassemia. Am J Hematol. 2016;91(11):1135-1145.
Editorials
at improving the balance between unbound a-globin and non-a-globin chains or correcting the ineffective erythro- poiesis. Modified TFG-β family receptor antagonists like Sotatercept (ACE-011) and Luspatercept (ACE-536) block ligand binding to ActR-II receptors, and subsequent activa- tion of the SMAD4 signaling pathway,4 improving ery- throid maturation and red cell production. Correction of the aberrant ratio of unbound a-globin to non-a-globin chains has been achieved by successful gene therapy by CRISPR Therapeutics, backed by Boston's Vertex Pharmaceuticals. The somatic cell therapy, named CTX001, uses edited patient’s own hematopoietic stem cells (HSC) to stimulate fetal hemoglobin production.5 Targeting intracellular local- ization of HSP70 via XPO1 inhibition potentially merges these two treatment goals.
study showing the novel mechanism of SINE as a poten- tial therapy for enhanced effective erythropoiesis in β- thalassemia. The clinical diversity of thalassemia makes it hard to design a one-size-fits-all therapy, and current therapies are mainly aimed at improving one or more of the underlying pathologies, most importantly transfusion dependence and iron overload. In this regard, a targeted inhibitor aimed at Xpo1 promises a more specific and low-risk treatment. Targeting HSP70 nuclear transloca- tion in erythroid precursors represents a novel and excit- ing therapeutic option to ameliorate the ineffective ery- thropoiesis of β-thalassemia.
References
Several lines of evidence suggest that erythroblasts use molecular chaperones to partition unstable excess a-glo- bin chains during erythroid development,6-8 so it follows that targeting such chaperones could be useful in β-tha- lassemia when excess a-globin tetramers accumulate and create havoc. Numerous groups have noted that the molecular chaperone Hsp70 accumulates to high levels in erythroblasts9-11 and are important for streamlining ery- throid maturation.11 Normal human erythroid maturation requires a transient activation of caspase-3 at the later stages of maturation in order to prevent excessive erythro- cyte production. Activated caspases can cleave GATA-1 leading to maturation arrest and/or apoptosis.12 Ribeil et al. showed that Epo causes Hsp70 to translocate into the nucleus, bind GATA-1, and protect it from caspase-3 cleavage. Conversely, during Epo deprivation, Hsp70 is excluded from the nucleus and GATA-1 is cleaved by cas- pase-3, causing apoptotic death.13 Thus, alteration of the intracellular location of Hsp70 appears to play a critical role in erythroblast viability (Figure 1).
1. De Sanctis V, Kattamis C, Canatan D, et al. β-thalassemia distribu- tion in the old world: an ancient disease seen from a historical stand- point. Mediterr J Hematol Infect Dis. 2017;9(1):e2017018.
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