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Blood, 1 January 2008, Vol. 111, No. 1, pp. 411-420. Prepublished online as a Blood First Edition Paper on October 4, 2007; DOI 10.1182/blood-2007-06-093948. This Article Full Text (PDF) All Versions of this Article: blood-2007-06-093948v1 111/1/411    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mabaera, R. Articles by Lowrey, C. H. Search for Related Content PubMed PubMed Citation Articles by Mabaera, R. Articles by Lowrey, C. H. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 6, 2007 Accepted September 21, 2007 Neither DNA hypomethylation nor changes in the kinetics of erythroid differentiation explain 5-azacytidine's ability to induce human fetal hemoglobin Rodwell Mabaera, Michael R. Greene, Christine A. Richardson, Sarah J. Conine, Courtney D. Kozul, and Christopher H. Lowrey* Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, United States Department of Medicine, Dartmouth Medical School, Hanover, NH, United States Norris Cotton Cancer Center, Darmouth-Hitchcock Medical Center, Lebanon, NH, United States * Corresponding author; email: c.lowrey{at}dartmouth.edu. 5-azacytidine (5-Aza) is a potent inducer of fetal hemoglobin (HbF) in people with -thalassemia and sickle cell disease. Two models have been proposed to explain this activity. The first is based on the drug's ability to inhibit global DNA methylation, including the fetal globin genes, resulting in their activation. The second is based on 5-Aza's cytotoxicity and observations that HbF production is enhanced during marrow recovery. We tested these models using human primary cells in an in vitro erythroid differentiation system. We found that doses of 5-Aza that produce near maximal induction of -globin mRNA and HbF do not alter cell growth, differentiation kinetics or cell cycle but do cause a localized demethylation of the promoter. However, when we reduced promoter methylation to levels equivalent to those seen with 5-Aza or to the lower levels seen in primary fetal erythroid cells using DNMT1 siRNA and shRNA, we observed no induction of -globin mRNA or HbF. These results suggest that 5-Aza induction of HbF is not the result of global DNA demethylation or of changes in differentiation kinetics, but involves an alternative, previously unrecognized mechanism. Other results suggest that post-transcriptional regulation plays an important role in the 5-Aza response. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: DNA methylation and mechanism of action of 5-azacytidine Donald Lavelle, Yogen Saunthararajah, and Joseph DeSimone Blood 2008 111: 2485. [Full Text] [PDF] Response: 5-azacytidine induction of human fetal hemoglobin Rodwell Mabaera and Christopher H. Lowrey Blood 2008 111: 2486. [Full Text] [PDF] Predicting outcome in childhood acute lymphoblastic leukemia using gene expression profiling: Prognostication or protocol selection? Daniel Catchpoole, Dachuan Guo, Honglin Jiang, and Cornelis Biesheuvel Blood 2008 111: 2486-2487. [Full Text] [PDF] This article has been cited by other articles: D. Lavelle, Y. Saunthararajah, and J. DeSimone DNA methylation and mechanism of action of 5-azacytidine Blood, February 15, 2008; 111(4): 2485 - 2485. [Full Text] [PDF] R. Mabaera and C. H. Lowrey Response: 5-azacytidine induction of human fetal hemoglobin Blood, February 15, 2008; 111(4): 2486 - 2486. [Full Text] [PDF]

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