Abstract
Induction of fetal hemoglobin (HbF) has therapeutic importance for patients with sickle cell disease (SCD) and the beta-thalassemias. It was recently reported that increased expression of LIN28 proteins or decreased expression of its target let-7 miRNAs enhances HbF levels in cultured primary human erythroblasts from adult healthy donors. Here LIN28A effects were studied further using erythrocytes cultured from peripheral blood progenitor cells of pediatric subjects with SCD. Transgenic expression of LIN28A was accomplished by lentiviral transduction in CD34(+) sickle cells cultivated ex vivo in serum-free medium. LIN28A over-expression (LIN28A-OE) increased HbF, reduced beta (sickle)-globin, and strongly suppressed all members of the let-7 family of miRNAs. LIN28A-OE did not affect erythroblast differentiation or prevent enucleation, but it significantly reduced or ameliorated the sickling morphologies of the enucleated erythrocytes.
Highlights
Sickle Cell Disease (SCD) and the beta-thalassemias are among the most prevalent genetic disorders worldwide with high levels of morbidity and mortality [1,2]
CD34(+) sickle cells Increased LIN28 in cultured erythroblasts from adult healthy donors causes increased gamma-globin gene and protein expression as they differentiate in culture [12]
The HbF content of the enucleated erythrocytes that are produced is elevated. To explore these effects in primary sickle cells, we investigated LIN28A-OE using erythroblasts from five children with SCD
Summary
Sickle Cell Disease (SCD) and the beta-thalassemias are among the most prevalent genetic disorders worldwide with high levels of morbidity and mortality [1,2]. Our understanding of these betahemoglobinopathies at both the clinical and molecular levels has increased greatly in recent decades [3]. Despite a homogeneous genetic mutation, clinical outcomes and response to therapy vary widely among patients with SCD [4]. HbF levels of 20% or greater are associated with improvements in the SCD patients’ clinical status [5]. Gene linkage studies associated BCL11A, HSB1L-MYB and HBB regions in the genome with increased HbF expression in adults [6,7,8,9], and suppression of BCL11A causes an increase in HbF levels and reverses the SCD phenotype in model systems [10,11]
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