Pathophysiology of thrombocytopenia and anemia in mice lacking transcription factor NF-E2

Expression of the p45 subunit of transcription factor NF-E2 is restricted t o selected blood cell lineages, including megakaryocytes and developing ery throcytes. Mice lacking p45 NF-EP show profound thrombocytopenia, resulting from a late arrest in megakaryocyte differentiation, and a number of red b lood cell defects, including anisocytosis and hypochromia, Here we report r esults of studies aimed to explore the pathophysiology of these abnormaliti es. Mice lacking NF-EP produce very few platelet-like particles that displa y highly disorganized ultrastructure and respond poorly to platelet agonist s, features consistent with the usually lethal hemorrhage in these animals. Thrombocytopenia was evident during fetal life and was not corrected by sp lenectomy in adults. Surprisingly, fetal NF-E2-deficient megakaryocyte prog enitors showed reduced proliferation potential in vitro. Thus, NF-ES is req uired for regulated megakaryocyte growth as well as for differentiation int o platelets. All the erythroid abnormalities were reproduced in lethally ir radiated wildtype recipients of hematopoietic cells derived from NF-E2-null fetuses. Whole blood from mice lacking p45 NF-E2 showed numerous small red blood cell fragments; however, survival of intact erythrocytes in vivo was indistinguishable from control mice. Considered together, these observatio ns indicate a requirement for NF-E2 in generating normal erythrocytes, Desp ite impressive splenomegaly at baseline, mice lacking p45 NF-ES survived sp lenectomy, which resulted in increased reticulocyte numbers. This reveals c onsiderable erythroid reserve within extra-splenic sites of hematopoiesis a nd suggests a role for the spleen in clearing abnormal erythrocytes, Our fi ndings address distinct aspects of the requirements for NF-E2 in blood cell homeostasis and establish its roles in proper differentiation of megakaryo cytes and erythrocytes. (C) 1999 by The American Society of Hematology.