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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 volume 20, pages 3651–3664 (2001)Cite this article

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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Author notes

  1. Marieke von Lindern and Eva Maria Deiner: M von Lindern and E M Deiner contributed equally to this work

Authors and Affiliations

  1. Institute of Hematology, Erasmus Medical Centre Rotterdam, PO Box 1738, DR Rotterdam, 3000, The Netherlands

    Marieke von Lindern & Martine Parren-van Amelsvoort

  2. Institute of Molecular Pathology, Dr. Bohrgasse 7, A-1030, Vienna, Austria

    Eva Maria Deiner & Hartmut Beug

  3. Institute of Medical Biochemistry, Vienna Biocenter (VBC), Dr. Bohr-Gasse 9, A-1030, Vienna, Austria

    Helmut Dolznig & Ernst W Mullner

  4. Department of Molecular Genetics & Microbiology, Life Sciences Bldg, State University of New York at Stony Brook, Stony Brook, 11794, New York NY, USA

    Michael J Hayman

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  1. Marieke von Lindern
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  2. Eva Maria Deiner
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  4. Martine Parren-van Amelsvoort
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Correspondence to Hartmut Beug.

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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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