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    A Cell-Based High-Throughput Screen for Novel Chemical Inducers of Fetal Hemoglobin for Treatment of Hemoglobinopathies

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    Issue Date
    2014-09-16
    Author
    Peterson, Kenneth R.
    Costa, Flávia C.
    Fedosyuk, Halyna
    Neades, Renee Y.
    Chazelle, Allen M.
    Zelenchuk, Lesya
    Fonteles, Andrea H.
    Dalal, Parmita
    Roy, Anuradha
    Chaguturu, Rathnam
    Li, Biaoru
    Pace, Betty S.
    Publisher
    Public Library of Science
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
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    Abstract
    Decades of research have established that the most effective treatment for sickle cell disease (SCD) is increased fetal hemoglobin (HbF). Identification of a drug specific for inducing c-globin expression in pediatric and adult patients, with minimal off-target effects, continues to be an elusive goal. One hurdle has been an assay amenable to a high-throughput screen (HTS) of chemicals that displays a robust c-globin off-on switch to identify potential lead compounds. Assay systems developed in our labs to understand the mechanisms underlying the c- to b-globin gene expression switch during development has allowed us to generate a cell-based assay that was adapted for a HTS of 121,035 compounds. Using chemical inducer of dimerization (CID)-dependent bone marrow cells (BMCs) derived from human c-globin promoter-firefly luciferase b-globin promoter-Renilla luciferase b-globin yeast artificial chromosome (c-luc b-luc b-YAC) transgenic mice, we were able to identify 232 lead chemical compounds that induced c-globin 2-fold or higher, with minimal or no b-globin induction, minimal cytotoxicity and that did not directly influence the luciferase enzyme. Secondary assays in CIDdependentwild-type b-YAC BMCs and human primary erythroid progenitor cells confirmed the induction profiles of sevenof the 232 hits that were cherry-picked for further analysis.
    Description
    This is the published version, also available here, http//dx.doi.org/10.1371/journal.pone.0107006.
    URI
    http://hdl.handle.net/1808/15538
    DOI
    https://doi.org/10.1371/journal.pone.0107006
    Collections
    • Publications [6]
    Citation
    Peterson KR, Costa FC, Fedosyuk H, Neades RY, Chazelle AM, et al. (2014) "A Cell-Based High-Throughput Screen for Novel Chemical Inducers of Fetal Hemoglobin for Treatment of Hemoglobinopathies." PLoS ONE 9(9): e107006. http://dx.doi.org/10.1371/journal.pone.0107006

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    KU Libraries
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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