The molecular mechanisms governing gamma-globin expression in a subset of fetal hemoglobin (alpha2:gamma2; HbF) expressing red blood cells (F-cells) and the mechanisms underlying the variability of response to hydroxyurea induced gamma-globin expression in the treatment of sickle cell disease are not completely understood. To explore molecular differences in these conditions, a serum-free in vitro culture system suitable for large scale production of erythroblasts derived from primary human hematopoietic progenitors is optimized. The culture system recapitulates steady-state adult erythropoiesis and can support erythroid differentiation with the addition of cytotoxic hydroxyurea. Using this system, intra-person clonal populations of erythroblasts derived from bone marrow common myeloid progenitors were evaluated for molecular factors associated with gamma-globin expression. Data demonstrate that the level of fetal hemoglobin produced in F-cells negatively correlates with expression of BCL11A, KLF1 and TALL With the addition of hydroxyurea, successful induction of gamma-globin includes a further reduction in BCL11 A, KLF1 and TALI expression along with a decrease in SOX6 expression. These data suggests that expression changes in this transcription factor network modulate gamma-globin expression in F-cells during steady state erythropoiesis and after induction with hydroxyurea.
|Advisor:||Bouhassira, Eric E.|
|School Location:||United States -- New York|
|Source:||DAI-B 77/12(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Aeronomy, Cellular biology|
|Keywords:||Definitive Erythropoiesis, F-Cells, Globin, Hemoglobin, Hydroxyurea, KLF1 BCL11A TAL1 SOX6|
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