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CLL

Chronic lymphocytic leukemia cells display p53-dependent drug-induced Puma upregulation

Leukemia volume 19, pages 427–434 (2005)Cite this article

Abstract

We investigated the apoptosis gene expression profile of chronic lymphocytic leukemia (CLL) cells in relation to (1) normal peripheral and tonsillar B-cell subsets, (2) IgVH mutation status, and (3) effects of cytotoxic drugs. In accord with their noncycling, antiapoptotic status in vivo, CLL cells displayed high constitutive expression of Bcl-2 and Flip mRNA, while Survivin, Bid and Bik were absent. Paradoxically, along with these antiapoptotic genes CLL cells had high-level expression of proapoptotic BH3-only proteins Bmf and Noxa. Treatment of CLL cells with fludarabine induced only the proapoptotic genes Bax and Puma in a p53-dependent manner. Interestingly, the degree of Puma induction was more pronounced in cells with mutated IgVH genes. Thus, disturbed apoptosis in CLL is the net result of both protective and sensitizing aberrations. This delicate balance can be tipped via induction of Puma in a p53-dependent matter, the level of which may vary between groups of patients with a different tendency for disease progression.

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Acknowledgements

The authors are indebted to the patients for their blood donations, and to technicians from the department of Hematology for technical assistance with patient material. Peripheral B cells were purified by Si-La Yong. Recombinant Puma-β protein was generated by Esther Beuling. The help and expertise of Lucien Aarden and Anja ten Brinke of Sanquin Research in obtaining the Puma antiserum is much appreciated. We are also grateful to Dr Laura Rassenti, Monica Cook, Lang Huynh, Traci Toy from the John and Rebecca Moores Cancer center for their technical assistance. This work was also supported by the Dutch Cancer Foundation (DCF) Grant 99-1998 to WJMM and AG, Grant 99-1996 to EE, a personal DCF Grant to APK and by Grant R37 CA49870 from the National Institute of Health.

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Author notes

  1. W J M Mackus and A P Kater: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    W J M Mackus, A P Kater, A Grummels, L M Evers & M H J van Oers

  2. Laboratory for Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    W J M Mackus, A P Kater, A Grummels, R A W van Lier & E Eldering

  3. John and Rebecca Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA

    A P Kater, J E Castro & T J Kipps

  4. Department of Clinical Viro-immunology, Sanquin Research at CLB, Amsterdam, The Netherlands

    B Hooijbrink

  5. Department of Internal Medicine, Meander Medical Center, Amersfoort, The Netherlands

    M H H Kramer

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  1. W J M Mackus
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Mackus, W., Kater, A., Grummels, A. et al. Chronic lymphocytic leukemia cells display p53-dependent drug-induced Puma upregulation. Leukemia 19, 427–434 (2005). https://doi.org/10.1038/sj.leu.2403623

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