• Characterization of the transcriptome profiles related to globin gene switching during in vitro erythroid maturation

      Li, Biaoru; Ding, Lianghao; Li, Wei; Story, Michael D; Pace, Betty S.; Department of Pediatrics (2012-04-26)
      Background: The fetal and adult globin genes in the human b-globin cluster on chromosome 11 are sequentially expressed to achieve normal hemoglobin switching during human development. The pharmacological induction of fetal g-globin (HBG) to replace abnormal adult sickle bS-globin is a successful strategy to treat sickle cell disease; however the molecular mechanism of g-gene silencing after birth is not fully understood. Therefore, we performed global gene expression profiling using primary erythroid progenitors grown from human peripheral blood mononuclear cells to characterize gene expression patterns during the g-globin to b-globin (g/b) switch observed throughout in vitro erythroid differentiation
    • FK228 Analogues Induce Fetal Hemoglobin in Human Erythroid Progenitors

      Makala, Levi HC; Di Maro, Salvatore; Lou, Tzu-Fang; Sivanand, Sharanya; Ahn, Jung-Mo; Pace, Betty S.; Department of Pediatrics (2012-05-14)
      Fetal hemoglobin (HbF) improves the clinical severity of sickle cell disease (SCD), therefore, research to identify HbF-inducing agents for treatment purposes is desirable. The focus of our study is to investigate the ability of FK228 analogues to induce HbF using a novel KU812 dual-luciferase reporter system. Molecular modeling studies showed that the structure of twenty FK228 analogues with isosteric substitutions did not disturb the global structure of the molecule. Using the dual-luciferase system, a subgroup of FK228 analogues was shown to be inducers of HbF at nanomolar concentrations. To determine the physiological relevance of these compounds, studies in primary erythroid progenitors confirmed that JMA26 and JMA33 activated HbF synthesis at levels comparable to FK228 with low cellular toxicity. These data support our lead compounds as potential therapeutic agents for further development in the treatment of SCD.
    • Sickle Cell Disease: Genetics, Cellular and Molecular Mechanisms, and Therapies

      Pace, Betty S.; Ofori-Acquah, Solomon F.; Peterson, Kenneth R.; Department of Pediatrics (2012-08-22)