The review provides an overview of recent data regarding the molecular players in β-thalassemia dyserythropoiesis and the corresponding therapeutic implications.
β-thalassemia dyserythropoiesis is characterized by four steps: expansion of erythroid progenitors, accelerated erythroid differentiation until the polychromatophilic stage, maturation arrest, and apoptosis at the polychromatophilic stage. Excess α-globin chains are the primary culprit in the disease, but the link between this excess and ineffective erythropoiesis has only recently been established. Important recent advances in understanding the molecular determinants involved in two critical steps of dyserythropoiesis are paving the way to new alternative targets for the treatment of this disease.
Growth differentiation factor 11 (GDF11) blockade increases the apoptosis of erythroblasts with excess α-chains by upregulating Fas-ligand in late basophilic and polychromatophilic erythroblasts, thereby decreasing cell expansion (step 1). Blocking GDF11 alleviates anemia in a mouse model of β-thalassemia and also in humans, most likely by promoting cells of ‘good’ erythroblastic lineage containing an α-/non-α-globin chain ratio of close to 1. Maturation arrest at the polychromatophilic stage (step 3) is associated with the depletion of GATA binding protein 1 (GATA-1) from the nucleus, which results from cytoplasmic sequestration of heat shock protein 70 (HSP70) by α-globin chains. Small molecules disrupting the HSP70/α-globin complex in the cytoplasm or decreasing HSP70 nuclear export might increase the nuclear localization of HSP70, thereby protecting GATA-1 and alleviating anemia. Finally, increasing the serum levels of hepcidin or transferrin alleviates anemia and dyserythropoiesis by diminishing iron uptake by erythroblasts in mouse models.
aLaboratoire INSERM UMR 1163, CNRS ERL 8254
bService de Médecine Interne, Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou
cParis Descartes-Sorbonne Paris Cité University, Imagine Institute, Assistance Publique-Hôpitaux de Paris, Hôpital Necker
dLaboratory of Excellence GR-Ex
eService d’Hématologie, Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris Hôpital Necker, Paris, France
*Olivier Hermine and Geneviève Courtois contributed equally to the writing of this article.
Correspondence to Olivier Hermine, MD, PhD, Laboratoire INSERM UMR 1163, CNRS ERL 8254, Institut Imagine, Université Sorbonne Paris Cité, Service d’Hématologie Adulte, Hôpital Necker, 161 Rue de Sèvres, 75743 Paris, France. Tel: +3 1 44490675; fax: +33 1 4449 0676; e-mail: email@example.com