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Ablation of miR‐144/451 disrupts homeostasis of erythropoiesis. Myc, a protooncogenic protein, is essential for erythroblast proliferation but commits rapid downregulation during erythroid maturation. How erythroblasts orchestrate maturation processes through coding and non‐coding genes is largely unknown. In this study, we use miR‐144/451 knockout mice as in vivo model, G1E, MEL erythroblast lines and erythroblasts from fresh mouse fetal livers as in vitro systems to demonstrate that targeted depletion of miR‐144/451 blocks erythroid nuclear condensation and enucleation. This is due, at least in part, to the continued high expression of Myc in erythroblasts when miR‐144/451 is absent. Specifically, miR‐144/451 directly inhibits Myc in erythroblasts. Loss of miR‐144/451 locus derepresses, and thus, increases the expression of Myc. Sustained high levels of Myc in miR‐144/451‐depleted erythroblasts blocks erythroid differentiation. Moreover, Myc reversely regulates the expression of miR‐144/451, forming a positive miR‐144/451‐Myc feedback to ensure the complete shutoff of Myc during erythropoiesis. Given that erythroid‐specific transcription factor GATA1 activates miR‐144/451 and inactivates Myc, our findings indicate that GATA1‐miR‐144/451‐Myc network safeguards normal erythroid differentiation. Our findings also demonstrate that disruption of the miR‐144/451‐Myc crosstalk causes anemia, suggesting that miR‐144/451 might be a potential therapeutic target in red cell diseases. [ABSTRACT FROM AUTHOR]