Human Molecular Genetics Advance Access published online on November 25, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddh023
© 2003 by Oxford University Press
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1 Cell and Gene Therapy Research Group, The Murdoch Childrens Research Institute, The University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville 3052, Melbourne, Australia
* To whom correspondence should be addressed. E-mail: panos.ioannou{at}mcri.edu.au.
Reactivation of fetal hemoglobin (HbF) expression using pharmacological agents represents a potential strategy for the therapy of
Article
Cellular genomic reporter assays for screening and evaluation of inducers of fetal hemoglobin
2 The Cyprus Institute of Neurology and Genetics, PO Box 3462, Nicosia, Cyprus
3 Cell and Gene Therapy Research Group, The Murdoch Childrens Research Institute, The University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville 3052, Melbourne, Australia; The Cyprus Institute of Neurology and Genetics, PO Box 3462, Nicosia, Cyprus
Abstract 
-thalassemia, sickle cell disease, HbE and other -hemoglobinopathies. However, the drugs currently available have low efficacy and specificity and are associated with high toxicity. We describe the development of stable cellular genomic reporter assays (GRAs) based on the green fluorescence protein (EGFP) gene under the G
-globin promoter in the intact human -globin locus. We show that human erythroleukemic cell lines stably transfected with a G-EGFP -globin locus construct can maintain a uniform basal level of EGFP expression over long periods of continuous culture and that induction of EGFP expression parallels the induction of the endogenous globin genes. We compared the EGFP-induction potency of a number of chemotherapeutic agents, including histone deacetylase inhibitors and DNA-binding agents. We show that hydroxyurea and butyrate result in moderate levels of induction (70-80%) but with an additive inductive effect. Among the DNA-binding agents tested, cisplatin was the most potent inducer of HbF expression, (442±32%), a level which is comparable to hemin (764±145%). These results indicate that cellular GRAs containing G-EGFP-modified -globin locus constructs can be used to develop novel inducers of HbF synthesis for the therapy of -hemoglobinopathies.
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