title: Expression and prognostic significance of the inhibitor of apoptosis protein (IAP) family and its antagonists in chronic lymphocytic leukaemia.
abstract: Impaired apoptosis is still considered to be an important event in the development and progression of chronic lymphocytic leukaemia (CLL). However, mechanisms of this defect have not been fully elucidated. In this study, expression of inhibitor of apoptosis proteins, IAPs (cIAP1, cIAP2, XIAP and survivin), and their antagonists (Smac/DIABLO and HtrA2/Omi) was comprehensively analysed in 100 untreated CLL patients, using flow cytometry and Western blot techniques. Expression of anti-apoptotic cIAP1 and cIAP2 in leukaemic cells was significantly higher than in non-tumour lymphocytes (p=0.000001 and p=0.014, respectively), whereas the IAP-antagonist, Smac/DIABLO, was decreased in CLL (p=0.010). Higher expression of all analysed IAPs (cIAP1, p=0.002; cIAP2, p=0.026; XIAP, p=0.002; survivin, p=0.00006) and lower levels of Smac/DIABLO (p=0.006) were found in patients with progressive disease, compared to those with stable CLL. High baseline expression of cIAP1 and survivin correlated with worse response to treatment. Co-expression of these proteins was associated with shorter overall survival of CLL patients (p=0.005). In conclusion, CLL cells show the apoptosis-resistant profile of IAPs/IAP-antagonist expression. Upregulation of IAPs is associated with a progressive course of the disease. Co-expression of cIAP1 and survivin seems to be an unfavourable prognostic factor in CLL patients. Further studies with longer follow up are warranted to confirm and expand these findings.
authors.affiliation: Department of Experimental Haematology, Medical University of Lodz, Copernicus Memorial Hospital, Ciolkowskiego 2, 93-510 Lodz, Poland.
authors.forename: Olga
authors.initials: O
authors.lastname: Grzybowska-Izydorczyk
authors.forename: Barbara
authors.initials: B
authors.lastname: Cebula
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Robak
authors.forename: Piotr
authors.initials: P
authors.lastname: Smolewski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor / Q000097:blood*; D018450:Disease Progression; D004812:Epidemiologic Methods; D005260:Female; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D016130:Immunophenotyping; D051034:Inhibitor of Apoptosis Proteins / Q000097:blood*; D047908:Intracellular Signaling Peptides and Proteins / Q000097:blood; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000097:blood; D009363:Neoplasm Proteins / Q000097:blood; D011379:Prognosis; D012697:Serine Endopeptidases / Q000097:blood; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2