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Induction of fetal hemoglobin (HbF) has therapeutic importance for patients with beta-hemoglobin disorders. Previous studies showed that  let-7  microRNAs (miRNAs) are highly regulated in erythroid cells during the fetal-to-adult developmental transition, and that targeting  let-7  mediated the up-regulation of HbF to greater than 30% of the total globin levels in human adult cultured erythroblasts. HMGA2 is a member of the high-mobility group A family of proteins and a validated target of the  let-7  family of miRNAs. Here we investigate whether expression of  HMGA2  directly regulates fetal hemoglobin in adult erythroblasts.  Let-7  resistant  HMGA2  expression was studied after lentiviral transduction of CD34(+) cells. The transgene was regulated by the erythroid-specific gene promoter region of the human  SPTA1  gene (HMGA2-OE). HMGA2-OE caused significant increases in  gamma-globin  mRNA expression and HbF to around 16% of the total hemoglobin levels compared to matched control transductions. Interestingly, no significant changes in  KLF1 ,  SOX6 ,  GATA1 ,  ZBTB7A  and  BCL11A  mRNA levels were observed. Overall, our data suggest that expression of HMGA2, a downstream target of  let-7  miRNAs, causes moderately increased  gamma-globin  gene and protein expression in adult human erythroblasts.

HMGA2 Moderately Increases Fetal Hemoglobin Expression in Human Adult Erythroblasts