A functional role of mitogen-activated protein kinases, Erk1 and Erk2, in the differentiation of a human leukemia cell line, UT-7/GM: A possible key factor for cell fate determination toward erythroid and megakaryocytic lineages

The mitogen-activated protein (MAP) kinase cascade is a kev regulator of ma mmalian cell proliferation and differentiation. In this study, we examined the roles of 2 members of the MAP kinase family, extracellular signal-regul ated kinase 1 (Erk1) and Erk2, in erythropoietin (EPO)-induced erythroid di fferentiation and thrombopoietin (TPO)-induced megakaryocytic differentiati on. UT-7/GM was used as a model system because this cell line is an erythro id/megakaryocytic bipotent cell line that can be induced to differentiate i nto the erythroid and megakaryocytic lineages by EPO and TPO, respectively. The kinetics of activation of Erk1 and Erk2 were examined during erythroid and megakaryocytic differentiation of UT-7/GM cells. EPO induced a transie nt activation of these kinases peaking after 1 minute of stimulation and th en declining quickly almost to the basal level. In contrast, TPO-induced ac tivation of the kinases peaked at 10 minutes and persisted for up to 60 min utes similar to the activation by granulocyte-macrophage colony-stimulating factor. The percentage of EPO-induced hemoglobin-positive cells was elevat ed by the addition of PD98059, a specific inhibitor of MEK1 (MAP kinase/ERK kinase 1). In contrast, PD98059 clearly reduced the amount of glycoprotein IIb/IIIa antigens induced by TPO on UT-7/GM cells. Thus, inactivation of E rk1 and Erk2 kinases promoted EPO-induced erythroid differentiation and sup pressed TPO-induced megakaryocytic differentiation of UT-7/GM cells. In con clusion, the activation of Erk1 and Erk2 kinases may be a critical event in the determination of cell fate and the differentiation processes of the er ythroid and megakaryocytic lineages. (C) 2001 The Japanese Society of Hemat ology.