In vitro studies have implicated the Lyn tyrosine kinase in erythropoietin signaling. In this study, we show that J2E erythroid cells lacking Lyn have impaired signaling and reduced levels of transcription factors STAT5a, EKLF and GATA-1. Since mice lacking STAT5, EKLF or GATA-1 have red cell abnormalities, this study also examined the erythroid compartment of Lyn À/À mice. Significantly, STAT5, EKLF and GATA-1 levels were appreciably lower in Lyn À/À erythroblasts, and the phenotype of Lyn À/À animals was remarkably similar to GATA-1 low animals. Although young adult Lyn-deficient mice had normal hematocrits, older mice developed anemia. Grossly enlarged erythroblasts and florid erythrophagocytosis were detected in the bone marrow of mice lacking Lyn. Markedly elevated erythroid progenitors and precursor levels were observed in the spleens, but not bone marrow, of Lyn À/À animals indicating that extramedullary erythropoiesis was occurring. These data indicate that Lyn À/À mice display extramedullary stress erythropoiesis to compensate for intrinsic and extrinsic erythroid defects.
J2E cells produce rapid, fatal erythroleukemias in vivo but still respond to erythropoietin (epo) in vitro by di erentiating, proliferating and remaining viable in the absence of serum. Mutant epo receptors were introduced into these cells to determine whether they could in¯uence the di erent biological responses to epo in vitro and the development of erythroleukemias. Three mutant receptors were used as cytoplasmic truncation mutants D257 and D321 (above box 1 and below box 2 respectively), and the cytoplasmic point mutant W282R (defective for JAK2 activation). Strikingly, the D321 mutation produced a hyper-sensitive response in vitro to epoinduced di erentiation and viability, but not to proliferation. In contrast with the D321 receptor, the D257 and W282R mutants inhibited all biological responses to epo due to impaired JAK2 phosphorylation. Signi®cantly, erythroleukemias took almost twice as long to develop with cells containing the W282R mutation, indicating that JAK2 plays an important role in the emergence of these leukemias. These data demonstrate that mutant epo receptors dominantly altered responses of J2E cells to epo in culture and the development of erythroleukemias. Oncogene (2000) 19, 953 ± 960.
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