Granulocyte-macrophage colony-stimulating factor reactivates fetal hemoglobin synthesis in erythroblast clones from normal adults.
Reactivation of fetal hemoglobin (HbF, alpha 2 gamma 2) synthesis was previously reported in normal human adult erythroblast colonies ("bursts") generated by erythroid progenitors (BFU-E) in fetal calf serum-supplemented (FCS+) semisolid cultures stimulated with erythropoietin (Ep). Our studies focused on the reactivation of HbF synthesis in normal adult erythroid bursts generated by peripheral blood mononuclear cells (PBMCs) seeded in FCS+ methylcellulose culture. Reactivation is almost totally suppressed when (a) PBMCs are grown in optimized FCS- culture, or (b) PBMCs are first stringently depleted of monocytes and then plated in FCS+ medium (ie, BFU-E growth in FCS+ Mo- culture). In both experimental conditions, the proliferation of lymphocytes and macrophages interspersed among colonies is drastically reduced, and the cloning efficiency of granulocyte-macrophage (GM) progenitors is sharply diminished. In either case, addition of biosynthetic GM colony-stimulating factor (GM-CSF) induces a dose-related increase of HbF synthesis up to the level in FCS+ culture, with even more elevated values on delayed addition of Ep. A dose-related increase was also observed in erythroblast clones generated by highly purified BFU-E. These results suggest that reactivation of HbF synthesis in normal adults is at least in part mediated by GM-CSF. Furthermore, they imply intriguing hypotheses on the mechanism(s) of perinatal Hb switching. Finally, they raise the possibility of reactivation of HbF synthesis in beta-thalassemia and sickle cell anemia by GM-CSF therapy.
Gabbianelli
M
M
Department of Hematology-Oncology, Istituto Superiore di Sanità Rome, Italy.
Pelosi
E
E
Bassano
E
E
Labbaye
C
C
Petti
S
S
Rocca
E
E
Tritarelli
E
E
Miller
B A
BA
Valtieri
M
M
Testa
U
U
D001685:Biological Factors / Q000494:pharmacology; D002478:Cells, Cultured; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D003470:Culture Media; D016207:Cytokines; D004305:Dose-Response Relationship, Drug; D004900:Erythroblasts / Q000378:metabolism*; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology; D005319:Fetal Hemoglobin / Q000096:biosynthesis*; D005914:Globins / Q000096:biosynthesis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007526:Isoelectric Point
D001685:Biological Factors; D003115:Colony-Stimulating Factors; D003470:Culture Media; D016207:Cytokines; D006133:Growth Substances; D004921:Erythropoietin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005914:Globins; D005319:Fetal Hemoglobin