Rapamycin-mediated induction of gamma-globin mRNA accumulation in human erythroid cells.
The present study aimed to determine whether rapamycin could increase the expression of gamma-globin genes in human erythroid cells. Rapamycin is a macrocyclic lactone that possesses immunosuppressive, antifungal and anti-tumour properties. This molecule is approved as an immunosuppressive agent for preventing rejection in patients receiving organ transplantation. To verify the activity of rapamycin, we employed two experimental cell systems, the human leukaemia K562 cell line and the two-phase liquid culture of human erythroid progenitors isolated from normal donors and patients with beta-thalassaemia. The results suggested that rapamycin, when compared with cytosine arabinoside, mithramycin and cisplatin, is a powerful inducer of erythroid differentiation and gamma-globin mRNA accumulation in human leukaemia K562 cells. In addition, when normal human erythroid precursors were cultured in the presence of rapamycin, gamma-globin mRNA accumulation and fetal haemoglobin (HbF) production increased to levels that were higher than those obtained using hydroxyurea. These effects were not associated with inhibition of cell growth. Furthermore, rapamycin was found to increase HbF content in erythroid precursor cells from four beta-thalassaemia patients. These results could have practical relevance, because pharmacologically mediated regulation of the expression of human gamma-globin genes, leading to increased HbF, is considered a potential therapeutic approach in haematological disorders, including beta-thalassaemia and sickle cell anaemia.
Mischiati
Carlo
C
Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy.
Sereni
Alessia
A
Lampronti
Ilaria
I
Bianchi
Nicoletta
N
Borgatti
Monica
M
Prus
Eugenia
E
Fibach
Eitan
E
Gambari
Roberto
R
D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000378:metabolism; D005914:Globins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D020014:K562 Cells; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology*; D017086:beta-Thalassemia / Q000378:metabolism
D012333:RNA, Messenger; D005914:Globins; D005319:Fetal Hemoglobin; D020123:Sirolimus