GSE192700
Aberrant Nrf2 activation delays erythroid maturation during chemotherapeutic drug-induced erythropoiesis
Nuclear factor (erythroid-derived 2)-like2 (Nrf2) and miR-144/451 regulate two well-established systems that have been identified to maintain redox homeostasis in erythroid cells by removing excess reactive oxygen species (ROS). Whether Nrf2 plays a role in the differentiation process during erythropoiesis has not been reported. In this study, we demonstrate that miR-144/451 gene knockout (KO) in mice dampens erythroid differentiation when 5-Fluorouridine is used to induce acute anemia. Surprisingly, inactivation of Nrf2 by crossing Nrf2 KO mice completely alleviates the delayed erythropoiesis in miR-144/451 KO mice. Nrf2 is a miR-144/451 target and depletion of miR-144/451 leads to the derepression of Nrf2, and thus an overexpression of Nrf2. Therefore, our findings indicate that persistent Nrf2 activation blocks erythroid maturation. We further reveal that even physiological levels of Nrf2 impair the erythroid differentiation. The underlying mechanism is that hyperactivity of Nrf2 leads to the sustained proliferation of erythroblasts partially by activation of Myc signaling. We also find that Nrf2 and miR-144/451 coordinate to scavenge ROS but do not phenotypically copy each other, indicating that they control two distinct anti-oxidant systems in erythroid cells. Furthermore, we find that miR-144/451 deficiency produces a more profound defect of erythropoiesis than dysfunctional Nrf2. Given that Nrf2 is ubiquitously expressed in tumor tissues, which facilitates cancer malignancy and chemoresistance; and that cancer is often accompanied by anemia that markedly inhibits antineoplastic treatment efficacy and anticancer immunity, our findings suggest that targeting Nrf2 holds great promise that not only harms cancer cells, but also reverses cancer-related anemia. Overall design: mRNAs from four groups of mouse erythroblasts derived from spleens 11 days after 5-FU treatment