Key Points• LIN28B regulates HbF expression in erythroblasts that are cultured from umbilical cord and adult human blood.• LIN28B expression manifested a more fetal-like phenotype among adult human erythroblasts.Reactivation of fetal hemoglobin (HbF) holds therapeutic potential for sickle cell disease and b-thalassemias. In human erythroid cells and hematopoietic organs, LIN28B and its targeted let-7 microRNA family, demonstrate regulated expression during the fetal-toadult developmental transition. To explore the effects of LIN28B in human erythroid cell development, lentiviral transduction was used to knockdown LIN28B expression in erythroblasts cultured from human umbilical cord CD341 cells. The subsequent reduction in LIN28B expression caused increased expression of let-7 and significantly reduced HbF expression. Conversely, LIN28B overexpression in cultured adult erythroblasts reduced the expression of let-7 and significantly increased HbF expression. Cellular maturation was maintained including enucleation. LIN28B expression in adult erythroblasts increased the expression of g-globin, and the HbF content of the cells rose to levels >30% of their hemoglobin. Expression of carbonic anhydrase I, glucosaminyl (N-acetyl) transferase 2, and miR-96 (three additional genes marking the transition from fetal-toadult erythropoiesis) were reduced by LIN28B expression. The transcription factor BCL11A, a well-characterized repressor of g-globin expression, was significantly down-regulated. Independent of LIN28B, experimental suppression of let-7 also reduced BCL11A expression and significantly increased HbF expression. LIN28B expression regulates HbF levels and causes adult human erythroblasts to differentiate with a more fetal-like phenotype. (Blood. 2013;122(6):1034-1041 IntroductionIn humans and some other mammals, the composition of hemoglobin tetramers in erythrocytes switch from fetal hemoglobin (HbF) (a2g2) to adult hemoglobin (HbA) (a2b2) during the last stages of fetal development until early infancy.1 HbF is the most important known modifier of the clinical symptoms for patients with sickle cell disease (SCD) and b-thalassemias, which are among the most common genetic disorders worldwide. 2,3 In patients with SCD, the polymerization of sickle hemoglobin results in erythrocyte deformation and hemolysis.4 SCD patient's clinical outcomes are largely improved by inhibition of the polymerization by HbF. 5 In b-thalassemias, decreased production of b-globin causes imbalanced globin polypeptide chain synthesis, and leads to severe effects on the erythroid cells' maturation and survival. The loss of b-globin expression may be compensated by an increase in HbF production that leads to improvement of the clinical phenotype. 6 The molecular mechanisms underlying the switch from HbF to HbA are still largely unknown. Genome-wide association studies (GWAS) in both normal individuals and patients with b-hemoglobinopathies have identified BCL11A, HSB1L-MYB, and HBB clusters as having an association with the persistence of Hb...

We recommend RCE plus chelation as an effective method for reducing iron overload, while maintaining HbS at 30% to 35%.

Key Points The G9a methyltransferase inhibitor UNC0638 increased pancellular expression of HbF to levels greater than 30% in adult human erythroblasts. UNC0638 altered globin locus epigenetic status/protein occupancy favoring LCR interaction with fetal genes at the expense of adult genes.