Pociredir inhibits polycomb repressive complex 2 and induces fetal hemoglobin in healthy and sickle cell disease models [dataset1]

ABSTRACT: Sickle cell disease (SCD) and b-thalassemias are caused by mutations in the hemoglobin b gene (HBB) that result in a dysfunctional adult hemoglobin protein. However, patients who harbor additional genetic alterations that elevate fetal hemoglobin (HbF) expression during adulthood experience reduced disease severity. Modest elevations in HbF provide clinical benefit, while substantial elevations appear to result in asymptomatic disease. Elucidating the regulatory networks controlling HbF expression is critical to the discovery of new therapies for SCD and b-thalassemias. B-cell lymphoma/leukemia 11A (BCL11A) has been shown to be a master regulator that suppresses expression of fetal hemoglobin genes (HBG1/2) in adults. We show that polycomb repressive complex 2 (PRC2) regulates BCL11A expression in erythroid progenitor cells and thus is a putative upstream regulator of HBG1/2 expression. Moreover, we demonstrate that negative modulation of PRC2 activity via different pharmacologic or genetic knockdown approaches results in decreased BCL11A expression and concomitant and robust increases in both HBG1/2 mRNA and HbF protein (or their orthologs) across in vitro and in vivo models of SCD. These novel findings further elucidate the regulatory network underlying HBG1/2 expression and have important implications for the use of PRC2 inhibitors as potential therapies for SCD and b-thalassemias. Inhibition of embryonic ectoderm development (EED), a key subunit of PRC2, was particularly effective in modulating the activity of the complex. The translation of these findings is underway as pociredir (FTX-6058), a novel and potent EED inhibitor, is currently being evaluated in clinical studies as a potential treatment for select hemoglobinopathies (NCT05169580).

ORGANISM(S): Homo sapiens

PROVIDER: GSE309131 | GEO | 2026/09/01

REPOSITORIES: GEO