XPO1 regulates erythroid differentiation and is a new target for the treatment of ß-thalassemia.
Haematologica
; 105(9): 2240-2249, 2020 09 01.
Article
in En
| MEDLINE
| ID: mdl-33054049
ABSTRACT
ß-thalassemia major (ß-TM) is an inherited hemoglobinopathy caused by a quantitative defect in the synthesis of ß-globin chains of hemoglobin, leading to the accumulation of free a-globin chains that aggregate and cause ineffective erythropoiesis. We have previously demonstrated that terminal erythroid maturation requires a transient activation of caspase-3 and that the chaperone Heat Shock Protein 70 (HSP70) accumulates in the nucleus to protect GATA-1 transcription factor from caspase-3 cleavage. This nuclear accumulation of HSP70 is inhibited in human ß-TM erythroblasts due to HSP70 sequestration in the cytoplasm by free a-globin chains, resulting in maturation arrest and apoptosis. Likewise, terminal maturation can be restored by transduction of a nuclear-targeted HSP70 mutant. Here we demonstrate that in normal erythroid progenitors, HSP70 localization is regulated by the exportin-1 (XPO1), and that treatment of ß-thalassemic erythroblasts with an XPO1 inhibitor increased the amount of nuclear HSP70, rescued GATA-1 expression and improved terminal differentiation, thus representing a new therapeutic option to ameliorate ineffective erythropoiesis of ß-TM.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Beta-Thalassemia
/
Receptors, Cytoplasmic and Nuclear
/
Karyopherins
Limits:
Humans
Language:
En
Journal:
Haematologica
Year:
2020
Document type:
Article