Hematopoiesis is systematically regulated by microenvironmental factors. The positive and negative factors coordinated together to yield a complicated blood system. Interferon-gamma (IFN gamma) has been identified as a common cause of various hematopoietic abnormalities, such as aplastic anemia. However, its impact on monolineage development, especially erythropoiesis, has not been fully elucidated from the cellular angle. In this study, we investigated the behavior of IFN gamma and found that IFN gamma plays dual functions on erythropoiesis; it not only blocks the erythroid lineage commitment but also accelerates the erythroid differentiation process, ultimately leading to the erythropoietic window clearance. IFN gamma can even powerfully initiate early differentiation without the existence of erythropoietin (EPO). Interferon regulatory factor 1 (IRF1) was confirmed as the essential downstream effector, and its ectopic overexpression can also have the same effect as that of IFN gamma. These results reveal that the IFN gamma-IRF1 axis plays a bidirectional role on erythropoiesis, impeding the access to erythroid lineage and driving the coming cells toward the differentiation endpoint. This model may place an innovative implication for IFN gamma-IRF1 axis to understand its in-depth mechanism on normal hematopoiesis and abnormal blood disorders, especially aplastic anemia. (C) 2019 Elsevier Inc. All rights reserved.