Abstract
Primary erythroid progenitors can be expanded by the synergistic action of erythropoietin (Epo), stem cell factor (SCF) and glucocorticoids. While Epo is required for erythropoiesis in general, glucocorticoids and SCF mainly contribute to stress erythropoiesis in hypoxic mice. This ability of normal erythroid progenitors to undergo expansion under stress conditions is targeted by the avian erythroblastosis virus (AEV), harboring the oncogenes v-ErbB and v-ErbA. We investigated the signaling pathways required for progenitor expansion under stress conditions and in leukemic transformation. Immortal strains of erythroid progenitors, able to undergo normal, terminal differentiation under appropriate conditions, were established from fetal livers of p53−/− mice. Expression and activation of the EGF-receptor (HER-1/c-ErbB) or its mutated oncogenic version (v-ErbB) in these cells abrogated the requirement for Epo and SCF in expansion of these progenitors and blocked terminal differentiation. Upon inhibition of ErbB function, differentiation into erythrocytes occurred. Signal transducing molecules important for renewal induction, i.e. Stat5- and phosphoinositide 3-kinase (PI3K), are utilized by both EpoR/c-Kit and v/c-ErbB. However, while v-ErbB transformed cells and normal progenitors depended on PI3K signaling for renewal, c-ErbB also induces progenitor expansion by PI3K-independent mechanisms.
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Acknowledgements
We thank Gabi Litos and Gabi Stengl for expert technical assistance. This work was supported by grants from the Austrian Forschungsförderungs fonds (FFF, Project No. 802447, HB), the Austrian Science Foundation (FWF, SFB006, HB, EM), the Dutch Cancer Society (EUR 95-1021), the European Community (HPRN-CT-2000-00083, HB, MvL and ERBFMRX-CT-98-0197, HB, EM) and by a fellowship of the Dutch Academy for Arts and Sciences (KNAW) to MvL.
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von Lindern, M., Deiner, E., Dolznig, H. et al. Leukemic transformation of normal murine erythroid progenitors: v- and c-ErbB act through signaling pathways activated by the EpoR and c-Kit in stress erythropoiesis. Oncogene 20, 3651–3664 (2001). https://doi.org/10.1038/sj.onc.1204494
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DOI: https://doi.org/10.1038/sj.onc.1204494
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