Abstract
Increasing fetal-type hemoglobin expression in adult erythroid cells holds promise in the treatment of sickle cell disease (SCD) and β-thalassemia. We have identified the MLL1 complex as a critical regulator of fetal and embryonic hemoglobin repression. Knockdowns of MEN1 and KMT2A, encoding essential components of the complex, caused a significant downregulation of BCL11A expression and a substantial increase in γ- and ε-globin mRNA levels in HUDEP-2 cells. Significant binding of MEN1 and KMT2A was readily detected at the promoter and a critical enhancer of BCL11A in HUDEP-2 cells, suggesting that BCL11A is a direct transcriptional target of the MLL1 complex. Consistent with these results, MEN1 or KMT2A knockdown in normal human CD34+ hematopoietic stem and progenitor cells induced to undergo erythroid differentiation also significantly decreased their BCL11A expression and increased their γ- and ε-globin expression and the production of F cells in the culture. Treatment of these cells with MENIN inhibitors yielded similar results and promoted erythroid differentiation with minimal effects on their growth. Moreover, treatment of CD34+ hematopoietic stem and progenitor cells from SCD patients with MENIN inhibitors substantially increased γ-globin expression in their erythroid progenies. These findings underscore a critical role of the MLL1 complex in regulating fetal and embryonic hemoglobin expression and suggest that MENIN inhibitors could offer a promising therapeutic approach for SCD and β-thalassemia.