OBJECTIVE: Augmentation of the level of fetal hemoglobin (HbF) is considered therapeutic for patients with sickle cell disease. The objective of this study was to determine the effect of treatment with a combination of erythropoietin (Epo), stem cell factor (SCF), and hydroxyurea (HU) on HbF levels. MATERIALS AND METHODS: The effect of treatment with a combination of Epo, SCF, and HU on HbF, F-cell numbers, and globin chain synthesis was evaluated in a baboon model. RESULTS: Treatment with a combination of SCF+Epo resulted in a two-fold increase in HbF, F-cells, and F-reticulocytes compared to Epo alone. The combination of SCF+Epo+HU resulted in an additional two-fold increase in HbF, whereas F-cells and F-reticulocytes increased only 25% compared to the SCF+Epo regimen. Measurement of differential globin chain synthesis indicated that the SCF+Epo+HU treatment also increased the I gamma/V gamma (homologous to human G gamma and A gamma) synthetic ratio toward the fetal ratio. CONCLUSIONS: HU can effectively augment growth factor-induced HbF synthesis in vivo. Because I gamma/V gamma ratios are unaffected by erythropoietic stress and similar increases in this ratio have only been observed following administration of 5-azacytidine, we suggest that these two agents may share a common mechanism of action involving the recruitment of a similar target cell population to terminal erythroid differentiation.
OBJECTIVE: Augmentation of the level of fetal hemoglobin (HbF) is considered therapeutic for patients with sickle cell disease. The objective of this study was to determine the effect of treatment with a combination of erythropoietin (Epo), stem cell factor (SCF), and hydroxyurea (HU) on HbF levels. MATERIALS AND METHODS: The effect of treatment with a combination of Epo, SCF, and HU on HbF, F-cell numbers, and globin chain synthesis was evaluated in a baboon model. RESULTS: Treatment with a combination of SCF+Epo resulted in a two-fold increase in HbF, F-cells, and F-reticulocytes compared to Epo alone. The combination of SCF+Epo+HU resulted in an additional two-fold increase in HbF, whereas F-cells and F-reticulocytes increased only 25% compared to the SCF+Epo regimen. Measurement of differential globin chain synthesis indicated that the SCF+Epo+HU treatment also increased the I gamma/V gamma (homologous to human G gamma and A gamma) synthetic ratio toward the fetal ratio. CONCLUSIONS: HU can effectively augment growth factor-induced HbF synthesis in vivo. Because I gamma/V gamma ratios are unaffected by erythropoietic stress and similar increases in this ratio have only been observed following administration of 5-azacytidine, we suggest that these two agents may share a common mechanism of action involving the recruitment of a similar target cell population to terminal erythroid differentiation.
Authors: Diego A Espinoza; Xing Fan; Di Yang; Stefan F Cordes; Lauren L Truitt; Katherine R Calvo; Idalia M Yabe; Selami Demirci; Kristin J Hope; So Gun Hong; Allen Krouse; Mark Metzger; Aylin Bonifacino; Rong Lu; Naoya Uchida; John F Tisdale; Xiaolin Wu; Suk See DeRavin; Harry L Malech; Robert E Donahue; Chuanfeng Wu; Cynthia E Dunbar Journal: Mol Ther Date: 2019-04-09 Impact factor: 11.454
Authors: Mei Hsu; Christine A Richardson; Emmanuel Olivier; Caihong Qiu; Eric E Bouhassira; Christopher H Lowrey; Steven Fiering Journal: Exp Hematol Date: 2009-05-19 Impact factor: 3.084
Authors: Xing Fan; Chuanfeng Wu; Lauren L Truitt; Diego A Espinoza; Stephanie Sellers; Aylin Bonifacino; Yifan Zhou; Stefan F Cordes; Allen Krouse; Mark Metzger; Robert E Donahue; Rong Lu; Cynthia E Dunbar Journal: Haematologica Date: 2019-10-03 Impact factor: 9.941