title: Silencing of APAF-1 in B-CLL results in poor prognosis in the case of concomitant p53 mutation.
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 (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.
authors.affiliation: Department of Hematology and Oncology, Charité, Campus Virchow Medical Center, Humboldt University, Berlin, Germany.
authors.forename: Isrid
authors.initials: I
authors.lastname: Sturm
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Bosanquet
authors.forename: Silke
authors.initials: S
authors.lastname: Radetzki
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Peter T
authors.initials: PT
authors.lastname: Daniel
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D004252:DNA Mutational Analysis; D005260:Female; D005720:Gamma Rays; D020869:Gene Expression Profiling; D020868:Gene Silencing; D016158:Genes, p53; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011506:Proteins / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: C506592:APAF1 protein, human; D000970:Antineoplastic Agents; D053477:Apoptotic Protease-Activating Factor 1; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger