Silencing of APAF-1 in B-CLL results in poor prognosis in the case of concomitant p53 mutation

Authors

  • Isrid Sturm,

    1. Department of Hematology and Oncology, Charité, Campus Virchow Medical Center, Humboldt University, Berlin, Germany
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    • The first two authors contributed equally to this paper.

  • Andrew G. Bosanquet,

    1. Bath Cancer Research, Royal United Hospital, Bath, BA1 3NG, United Kingdom
    2. Department of Medical Sciences, University of Bath, BA2 7AY, United Kingdom
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    • The first two authors contributed equally to this paper.

  • Silke Radetzki,

    1. Department of Hematology and Oncology, Charité, Campus Virchow Medical Center, Humboldt University, Berlin, Germany
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  • Michael Hummel,

    1. Institute of Pathology, Charité, Campus Benjamin Franklin, Free University, Berlin, Germany
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  • Bernd Dörken,

    1. Department of Hematology and Oncology, Charité, Campus Virchow Medical Center, Humboldt University, Berlin, Germany
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  • Peter T. Daniel

    Corresponding author
    1. Department of Hematology and Oncology, Charité, Campus Virchow Medical Center, Humboldt University, Berlin, Germany
    • Clincal and Molecular Oncology, Charité - Campus Virchow Klinikum, Humboldt-University, Augustenburger Platz 1, 13353 Berlin, Germany
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    • Fax: +49-30-450-553963


Abstract

Apoptosis protease-activating factor 1 (APAF-1), a transcriptional target of p53, is a cytosolic adaptor protein that links the mitochondrial apoptosis pathway to the caspase cascade. Here, we aimed to study the impact of APAF-1 expression levels on cell death induced by anticancer drugs or ionizing irradiation (IR) and disease prognosis in B-type chronic lymphocytic leukemia (B-CLL) patients. Samples from 138 patients with B-CLL were investigated for APAF-1 expression and p53 mutations. The results were related to survival data, in vitro cytotoxicity of various cytotoxic drugs and IR and clinico-pathological data. Variable APAF-1 expression was observed in all investigated B-CLL samples. Reduction in APAF-1 expression was observed at both mRNA and protein level indicating transcriptional silencing whereas mutation of p53 or the immunoglobulin heavy chain variable genes (IgHV) had no impact on APAF-1 expression. Surprisingly, APAF-1 loss did not result in resistance to cytotoxic therapies. Likewise, APAF-1 downregulation on its own showed no impact on disease prognosis. Nevertheless, a poor prognosis was observed in patients with loss of APAF-1 expression and additional p53 mutation. Thus, loss of APAF-1 may become relevant when additional core apoptosis signaling components are disrupted. © 2005 Wiley-Liss, Inc.

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