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Chronic Lymphocytic Leukemia and B Cells

High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia

Leukemia volume 20, pages 498–504 (2006)Cite this article

Abstract

Chronic lymphocytic leukemia (CLL)-B-cells are quiescent differentiated cells that produce interleukin (IL)-10 and accumulate due to resistance to apoptosis. The mechanisms underlying such resistance are poorly understood. Herein we show that all CLL B-cells tested (30/30) display high mRNA and protein expression of the tumor suppressor Mda-7/IL-24, an IL-10 family member, in comparison to normal B cells. A downstream Mda-7 signaling target, p38 mitogen-activated protein kinase (MAPK) was highly phosphorylated in all CLL cells but not in normal B-cells. Mda-7 expression and p38 MAPK phosphorylation diminished in culture and the latter could be reinduced by recombinant (r)-IL-24 or LPS and Mda-7 transfection. Mda-7/IL-24 siRNA specifically inhibited p38 MAPK phosphorylation in CLL without affecting p38 MAPK, bcl2, or Lyn expression, further demonstrating the direct role of Mda-7/IL-24 in p38 MAPK activation. Both pharmacological inhibition of p38 MAPK and Mda-7 silencing augmented spontaneous apoptosis by three-fold in CLL cells cultured in autologous serum, which was reversed by LPS and r-IL-24. We established the role of p38 MAPK in CLL cell survival and demonstrated a paradoxical effect, whereby Mda-7 and IL-24, inducers of apoptosis in diverse cancer cells, promote the survival of CLL B-cells through p38 MAPK activation.

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Acknowledgements

Françoise Gaudin and Hervé Strub are acknowledged for technical help. This work was supported by two grants from the ‘Association de Recherche contre le Cancer’, ARC, and SIDACTION.

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Author notes

  1. A Sainz-Perez and H Gary-Gouy: These two authors contributed equally to this work.

Authors and Affiliations

  1. INSERM Unité 131, IFR 13, Université Paris XI 32 Rue des Carnets, Clamart, France

    A Sainz-Perez, H Gary-Gouy, A Portier, P Galanaud & A Dalloul

  2. Laboratoire d’Hématologie, Hôpital de la Pitié-Salpêtrière, Paris, France

    F Davi & H Merle-Beral

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  1. A Sainz-Perez
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Correspondence to A Dalloul.

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Sainz-Perez, A., Gary-Gouy, H., Portier, A. et al. High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia. Leukemia 20, 498–504 (2006). https://doi.org/10.1038/sj.leu.2404073

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