MLL1 complex is a critical regulator of fetal hemoglobin repression

Abstract

Increasing fetal-type hemoglobin (HbF) expression in adult erythroid cells holds promise in the treatment of sickle cell disease (SCD) and {beta}-thalassemia. We have identified 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 {gamma}- and {varepsilon}-globin mRNA levels in HUDEP-2 cells. Significant binding of MEN1 and KMT2A were readily detected at the promoter and a critical enhancer of BCL11A in HUDEP-2 cells, suggesting that BCL11A is a direct transcriptional target of MLL1 complex. Consistent with these results, MEN1 or KMT2A knockdown in normal human CD34+ hematopoietic stem and progenitor cells (HSPCs) induced to undergo erythroid differentiation also significantly decreased their BCL11A expression and increased their {gamma}- and {varepsilon}-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. These findings underscore a critical role of MLL1 complex in regulating fetal and embryonic hemoglobin expression and suggest that MENIN inhibitors could offer a promising therapeutic approach for sickle cell disease and {beta}-thalassemia.