• MYB depletion reactivates embryonic ζ-globin in mouse models and human hematopoietic stem cells, offering a therapeutic avenue for α-thalassemia and sickle cell disease.
• ETO2 is identified as a novel repressor of ζ-globin, acting via the NuRD complex to modulate histone deacetylation.
• The MYB-ETO2 axis co-regulates key erythroid genes more prominently than MYB-KLF1, highlighting a distinct transcriptional mechanism.
• ETO2 knockout in primary CD34+ cells from hemoglobin H patients significantly increases ζ-globin expression, and the MYB-ETO2 pathway primarily silences ζ-globin independent of BCL11A.