Author(s): Lee YT, de Vasconcellos JF, Yuan J, Byrnes C, Noh S, et al.
Reactivation of fetal hemoglobin (HbF) holds therapeutic potential for sickle cell disease and β-thalassemias. In human erythroid cells and hematopoietic organs, LIN28B and its targeted let-7 microRNA family, demonstrate regulated expression during the fetal-to-adult 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 CD34+ 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 γ-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-to-adult erythropoiesis) were reduced by LIN28B expression. The transcription factor BCL11A, a well-characterized repressor of γ-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.
Author(s): Lacalle RA, Pulido D, Vara J, Zaiacaín M, Jiménez A
Author(s): Lanza AM, Kim DS, Alper HS
Author(s): Ali N, Karlsson C, Aspling M, Hu G, Hacohen N, et al.
Author(s): Sims D, Mendes-Pereira AM, Frankum J, Burgess D, Cerone MA
Author(s): de Vasconcellos JF, Lee YT, Byrnes C, Tumburu L, Miller JL
Author(s): Lee YT, de Vasconcellos JF, Byrnes C, Kaushal M, Miller JL
Author(s): Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C
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