title: Epigenetic and molecular profiles of erythroid cells after hydroxyurea treatment in sickle cell anemia.
abstract: Hydroxyurea has been shown to be efficacious for the treatment of sickle cell anemia (SCA), primarily through the induction of fetal hemoglobin (HbF). However, the exact mechanisms by which hydroxyurea can induce HbF remain incompletely defined, although direct transcriptional effects and altered cell cycle kinetics have been proposed. In this study, we investigated potential epigenetic and alternative molecular mechanisms of hydroxyurea-mediated HbF induction by examining methylation patterns within the (G)γ-globin promoter and miRNA expression within primary CD71(+) erythrocytes of patients with SCA, both at baseline before beginning hydroxyurea therapy and after reaching maximum tolerated dose (MTD). Using both cross-sectional analysis and paired-sample analysis, we found that the highly methylated (G)γ-globin promoter was inversely correlated to baseline HbF levels, but only slightly altered by hydroxyurea treatment. Conversely, expression of several specific miRNAs was significantly increased after hydroxyurea treatment, and expression of miR-26b and miR-151-3p were both associated with HbF levels at MTD. The significant associations identified in these studies suggest that methylation may be important for regulation of baseline HbF, but not after hydroxyurea treatment, whereas changes in miRNA expression may be associated with hydroxyurea-mediated HbF induction. This study was registered at ClinicalTrials.gov (NCT00305175).
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA. aisha.walker@stjude.org
authors.forename: Aisha L
authors.initials: AL
authors.lastname: Walker
authors.forename: Shirley
authors.initials: S
authors.lastname: Steward
authors.forename: Thad A
authors.initials: TA
authors.lastname: Howard
authors.forename: Nicole
authors.initials: N
authors.lastname: Mortier
authors.forename: Matthew
authors.initials: M
authors.lastname: Smeltzer
authors.forename: Yong-Dong
authors.initials: YD
authors.lastname: Wang
authors.forename: Russell E
authors.initials: RE
authors.lastname: Ware
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000235:genetics*; D000986:Antisickling Agents / Q000627:therapeutic use; D002648:Child; D018899:CpG Islands / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects*; D004912:Erythrocytes / Q000187:drug effects / Q000502:physiology; D041905:Erythroid Cells / Q000187:drug effects*; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use*; D035683:MicroRNAs / Q000235:genetics; D011446:Prospective Studies; D012156:Reticulocytes / Q000187:drug effects / Q000502:physiology
chemical_list: D000986:Antisickling Agents; D035683:MicroRNAs; D005319:Fetal Hemoglobin; D006918:Hydroxyurea