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The mRNA-Binding Protein IGF2BP1 Restores Fetal Hemoglobin in Cultured Erythroid Cells from Patients with ?-Hemoglobin Disorders.


ABSTRACT: Sickle cell disease (SCD) and ?-thalassemia are caused by structural abnormality or inadequate production of adult hemoglobin (HbA, ?2?2), respectively. Individuals with either disorder are asymptomatic before birth because fetal hemoglobin (HbF, ?2?2) 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 ?-thalassemia or potently suppress expression of sickle ?-globin in SCD. In all cases, fetal ?-globin mRNA increased and adult ?-globin decreased due, in part, to formation of contacts between the locus control region (LCR) and ?-globin genes. We conclude that expression of IGF2BP1 in adult erythroid cells has the potential to maximize HbF expression in patients with severe ?-hemoglobin disorders by reversing the developmental ?- to ?-globin switch.

SUBMITTER: Chambers CB 

PROVIDER: S-EPMC7056608 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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The mRNA-Binding Protein IGF2BP1 Restores Fetal Hemoglobin in Cultured Erythroid Cells from Patients with β-Hemoglobin Disorders.

Chambers Christopher B CB   Gross Jeffrey J   Pratt Katherine K   Guo Xiang X   Byrnes Colleen C   Lee Y Terry YT   Lavelle Donald D   Dean Ann A   Miller Jeffery L JL   Wilber Andrew A  

Molecular therapy. Methods & clinical development 20200131


Sickle cell disease (SCD) and β-thalassemia are caused by structural abnormality or inadequate production of adult hemoglobin (HbA, α<sub>2</sub>β<sub>2</sub>), respectively. Individuals with either disorder are asymptomatic before birth because fetal hemoglobin (HbF, α<sub>2</sub>γ<sub>2</sub>) 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  ...[more]

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