title: Hydroxyurea responsiveness in β-thalassemic patients is determined by the stress response adaptation of erythroid progenitors and their differentiation propensity.
abstract: β-thalassemia is caused by mutations in the β-globin locus resulting in loss of, or reduced, hemoglobin A (adult hemoglobin, HbA, α2β2) production. Hydroxyurea treatment increases fetal γ-globin (fetal hemoglobin, HbF, α2γ2) expression in postnatal life substituting for the missing adult β-globin and is, therefore, an attractive therapeutic approach. Patients treated with hydroxyurea fall into three categories: i) 'responders' who increase hemoglobin to therapeutic levels; (ii) 'moderate-responders' who increase hemoglobin levels but still need transfusions at longer intervals; and (iii) 'non-responders' who do not reach adequate hemoglobin levels and remain transfusion-dependent. The mechanisms underlying these differential responses remain largely unclear. We generated RNA expression profiles from erythroblast progenitors of 8 responder and 8 non-responder β-thalassemia patients. These profiles revealed that hydroxyurea treatment induced differential expression of many genes in cells from non-responders while it had little impact on cells from responders. Part of the gene program up-regulated by hydroxyurea in non-responders was already highly expressed in responders before hydroxyurea treatment. Baseline HbF expression was low in non-responders, and hydroxyurea treatment induced significant cell death. We conclude that cells from responders have adapted well to constitutive stress conditions and display a propensity to proceed to the erythroid differentiation program.
authors.affiliation: Department of Cell Biology Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Farzin
authors.initials: F
authors.lastname: Pourfarzad
authors.forename: Marieke
authors.initials: M
authors.lastname: von Lindern
authors.forename: Azita
authors.initials: A
authors.lastname: Azarkeivan
authors.forename: Jun
authors.initials: J
authors.lastname: Hou
authors.forename: Sima Kheradmand
authors.initials: SK
authors.lastname: Kia
authors.forename: Fatemehsadat
authors.initials: F
authors.lastname: Esteghamat
authors.forename: Wilfred
authors.initials: W
authors.lastname: van Ijcken
authors.forename: Sjaak
authors.initials: S
authors.lastname: Philipsen
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.forename: Frank
authors.initials: F
authors.lastname: Grosveld
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics; D000220:Adaptation, Biological / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation; D016000:Cluster Analysis; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056426:Genetic Loci; D006441:Hemoglobin A / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use*; D013312:Stress, Physiological / Q000235:genetics; D016896:Treatment Outcome; D017086:beta-Thalassemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D055545:gamma-Globins / Q000235:genetics
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D055545:gamma-Globins; D006441:Hemoglobin A; D005319:Fetal Hemoglobin; D020727:ADP-Ribosylation Factors; D006918:Hydroxyurea