Sickle cell disease (SCD) and β-thalassemia are caused by structural abnormality or inadequate production of adult hemoglobin (HbA, α₂β₂), respectively. Individuals with either disorder are asymptomatic before birth because fetal hemoglobin (HbF, α₂γ₂) is unaffected. Thus, reversal of the switch from HbF to HbA could reduce or even prevent symptoms these disorders. In this study, we show that insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is one factor that could accomplish this goal. IGF2BP1 is a fetal factor that undergoes a transcriptional switch consistent with the transition from HbF to HbA. Lentivirus delivery of IGF2BP1 to CD34⁺ cells of healthy adult donors reversed hemoglobin production toward the fetal type in culture-differentiated erythroid cells. Analogous studies using patient-derived CD34⁺ cells revealed that IGF2BP1-dependent HbF induction could ameliorate the chain imbalance in β-thalassemia or potently suppress expression of sickle β-globin in SCD. In all cases, fetal γ-globin mRNA increased and adult β-globin decreased due, in part, to formation of contacts between the locus control region (LCR) and γ-globin genes. We conclude that expression of IGF2BP1 in adult erythroid cells has the potential to maximize HbF expression in patients with severe β-hemoglobin disorders by reversing the developmental γ- to β-globin switch.

镰状细胞病（SCD）和β地中海贫血由结构异常或产生不足成人血红蛋白引起的（HBA，α ₂ β ₂分别地）。与任一障碍的个体是无症状的出生前因为胎儿血红蛋白（HbF的，α ₂ γ ₂）不受影响。因此，从HbF切换到HbA的逆转可以减轻甚至预防这些疾病的症状。在这项研究中，我们表明胰岛素样生长因子2 mRNA结合蛋白1（IGF2BP1）是可以实现此目标的因素之一。IGF2BP1是一种胎儿因子，其转录转换与从HbF到HbA的转变一致。IGF2BP1的慢病毒传递至CD34 ⁺健康的成人供体细胞在培养分化的类红细胞中将血红蛋白的产生逆转为胎儿型。使用患者来源的CD34 ⁺细胞进行的类似研究表明，依赖IGF2BP1的HbF诱导可以减轻β地中海贫血中的链失衡或有效抑制SCD中镰刀β-珠蛋白的表达。在所有情况下，胎儿γ-珠蛋白mRNA增加而成人β-珠蛋白减少，部分原因是基因座控制区（LCR）和γ-珠蛋白基因之间形成接触。我们得出的结论是，通过逆转发育中的γ-向β-球蛋白的转换，在成年红细胞中IGF2BP1的表达具有使重度β-血红蛋白疾病患者中HbF表达最大化的潜力。