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Silencing of APAF‐1 in B‐CLL results in poor prognosis in the case of concomitant p53 mutation
Author(s) -
Sturm Isrid,
Bosanquet Andrew G.,
Radetzki Silke,
Hummel Michael,
Dörken Bernd,
Daniel Peter T.
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21535
Subject(s) - gene silencing , biology , cancer research , apoptosis , mutation , chronic lymphocytic leukemia , caspase , microbiology and biotechnology , programmed cell death , gene , immunology , leukemia , genetics
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 (IgH V ) 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.