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A sustained activation of PI3K/NF-κB pathway is critical for the survival of chronic lymphocytic leukemia B cells

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Abstract

The progressive rise of mature CD5+ B lymphocytes, despite the low proportion of proliferating cells, has led to the notion that B cell chronic lymphocytic leukemia (B-CLL) is primarily related to defective apoptosis. The microenvironment likely plays a prominent role because the malignant cells progressively accumulate in vivo, whereas they rapidly undergo spontaneous apoptosis when cultured in vitro. To assess microenvironment-mediated survival signals, B-CLL cells were cultured with a murine fibroblast cell line, Ltk−, with and without an agonistic antibody to CD40. Spontaneous apoptosis was associated with the loss of Akt and NF-κB activities. Interactions with fibroblasts sustained a basal level of Akt and NF-κB activities, which was dependent on phosphatidylinositol-3 kinase (PI3K). Constitutive activity of the PI3K pathway in B-CLL cells when cultured with fibroblasts prevented the downregulation of the prosurvival Bcl-2 family protein Bcl-xL and the caspase inhibitor proteins FLIPL and XIAP, and consequently caspase-3 activation and apoptosis. CD40 crosslinking in B-CLL cells did not further prevent murine fibroblasts-mediated apoptosis but induced cell proliferation, which was associated with an increase of Akt and NF-κB activation compared with cells cultured with fibroblasts alone. The PI3K pathway seems to play a pivotal role in B-CLL cell survival and growth.

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Acknowledgements

We thank the contribution to the study of B Contreras, I Losada, T Martín, I Martín-Larrauri, and S Rosado from Fundación LAIR; MJ Citores and C Puerta from Hospital Puerta de Hierro; and A Maraver and JF Rodríguez from Centro Nacional de Biotecnología; and Marta Pulido, MD, for editing the manuscript and editorial assistance. This work was supported by Fundación LAIR, Madrid, Spain.

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  1. A Durántez: Alberto Durántez passed away on 10 January 2003.

Authors and Affiliations

  1. Fundación LAIR, Madrid, Spain

    S Cuní, P Pérez-Aciego, G Pérez-Chacón & A Durántez

  2. Servicio de Medicina Interna I, Hospital Universitario Puerta de Hierro, Madrid, Spain

    J A Vargas & A Durántez

  3. Servicio de Neuro-inmunología, Hospital Universitario Puerta de Hierro, Madrid, Spain

    A Sánchez

  4. Unidad de Regulación Génica, Instituto de Salud Carlos III, Madrid, Spain

    F M Martín-Saavedra & S Ballester

  5. Servicio de Hematología, Hospital Universitario Puerta de Hierro, Madrid, Spain

    J García-Marco

  6. Servicio de Hematología, Hospital Clínico Universitario San Carlos, Madrid, Spain

    J Jordá

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Cuní, S., Pérez-Aciego, P., Pérez-Chacón, G. et al. A sustained activation of PI3K/NF-κB pathway is critical for the survival of chronic lymphocytic leukemia B cells. Leukemia 18, 1391–1400 (2004). https://doi.org/10.1038/sj.leu.2403398

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