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A survey of the signaling pathways involved in megakaryocytic differentiation of the human K562 leukemia cell line by molecular and c-DNA array analysis

Oncogene volume 25, pages 781–794 (2006)Cite this article

Abstract

The K562 cell line serves as a model to study the molecular mechanisms associated with leukemia differentiation. We show here that cotreatment of K562 cells with PMA and low doses of SB202190 (SB), an inhibitor of the p38 MAPK pathway, induced a majority of cells to differentiate towards the megakaryocytic lineage. Electronic microscopy analysis showed that K562 cells treated with PMA+SB exhibited characteristic features of physiological megakaryocytic differentiation including the presence of vacuoles and demarcation membranes. Differentiation was also accompanied by a net increase in megakaryocytic markers and a reduction of erythroid markers, especially when both effectors were present. PMA effect was selectively mediated by new PKC isoforms. Differentiation of K562 cells by the combination of PMA and SB required Erk1/2 activation, a threshold of JNK activation and p38 MAPK inhibition. Interestingly, higher concentrations of SB, which drastically activated JNK, blocked megakaryocytic differentiation, and considerably increased cell death in the presence of PMA. c-DNA microarray membranes and PCR analysis allow us to identify a set of genes modulated during PMA-induced K562 cell differentiation. Several gene families identified in our screening, including ephrins receptors and some angiogenic factors, had never been reported so far to be regulated during megakaryocytic differentiation.

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Acknowledgements

This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Ligue Nationale contre le Cancer (Equipe labellisée), and the Canceropole PACA. SM is a recipient from the LNC.

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Authors and Affiliations

  1. INSERM U526, Physiopathologie de la Survie et de la Mort Cellulaires, Equipe Labellisée par la Ligue Nationale contre le Cancer, Université de Nice Sophia-Antipolis, IFR50, Faculté de Médecine, Avenue de Valombrose, Nice, Cedex 2, 06107, France

    A Jacquel, M Herrant, N Belhacene, P Colosetti, S Marchetti & P Auberger

  2. Institut de Pharmacologie Moleculaire et Cellulaire UMR 6097 Centre National de la Recherche Scientifique, 660 Route des Lucioles, Valbonne, 06560, France

    V Defamie & B Mari

  3. Service d'Hématologie, Hôpital de l'Archet, 151 route de Saint-Antoine de Ginestiere, BP3079, Nice, Cedex 2, 06202, France

    L Legros & J-P Cassuto

  4. INSERM U576, Hopital de l'Archet, 151 route de Saint-Antoine de Ginestière, Nice, 06202, France

    M Deckert

  5. INSERM U721 Université de Nice Sophia-Antipolis, IFR50, Faculté de Médecine, Avenue de Valombrose, Nice, Cedex 2, 06107, France

    P Hofman

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  1. A Jacquel
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  2. M Herrant
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Correspondence to P Auberger.

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Jacquel, A., Herrant, M., Defamie, V. et al. A survey of the signaling pathways involved in megakaryocytic differentiation of the human K562 leukemia cell line by molecular and c-DNA array analysis. Oncogene 25, 781–794 (2006). https://doi.org/10.1038/sj.onc.1209119

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