title: Absence or low expression of fas-associated protein with death domain in acute myeloid leukemia cells predicts resistance to chemotherapy and poor outcome.
abstract: In acute myeloid leukemia (AML), coexpression of death receptors and ligands of the tumor necrosis factor (TNF) receptor/TNF-alpha superfamily on leukemic cells after chemotherapy is not always accompanied by apoptosis, suggesting that the apoptotic death receptor signaling pathway is disrupted. Because Fas-associated protein with death domain (FADD) is the main adaptor for transmitting the Fas, TNF-related apoptosis-inducing ligand receptors, and TNF receptor 1 death signal, expression of FADD was analyzed by Western blot and immunocytochemistry in leukemic cells of 70 de novo AML patients treated with the European Organization of Research and Treatment of Cancer AML-10 randomized trial before initiation of induction chemotherapy. Thirty seven percent of patients (17 of 46) with FADD negative/low (FADD(-/low)) leukemic cells had a primary refractory disease compared with 12% of FADD(+) patients (3 of 24; P = 0.05). FADD(-/low) expression was significantly associated with a worse event-free survival [EFS (P = 0.04)] and overall survival (P = 0.04). In multivariate analysis, FADD(-/low) protein expression was independently associated with a poor EFS and overall survival (P = 0.002 and P = 0.026, respectively). Importantly, FADD(-/low) protein expression predicted poor EFS even in patients with standard- or good-risk AML (P = 0.009). Thus, we identified low or absent expression of the FADD protein in leukemic cells at diagnosis as a poor independent prognostic factor that can predict worse clinical outcome even for patients with standard- or good-risk AML.
authors.affiliation: Département d'Immunologie, Institut Cochin, Institut National de la Santé et de la Recherche Médicale U 567, Centre National de Recherche Scientifique UMR 8104, Institut Fédératif de Recherche 116, Université René Descartes, Paris V, France.
authors.forename: Léa
authors.initials: L
authors.lastname: Tourneur
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Delluc
authors.forename: Vincent
authors.initials: V
authors.lastname: Lévy
authors.forename: Françoise
authors.initials: F
authors.lastname: Valensi
authors.forename: Isabelle
authors.initials: I
authors.lastname: Radford-Weiss
authors.forename: Ollivier
authors.initials: O
authors.lastname: Legrand
authors.forename: Jacques
authors.initials: J
authors.lastname: Vargaftig
authors.forename: Charlotte
authors.initials: C
authors.lastname: Boix
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Macintyre
authors.forename: Bruno
authors.initials: B
authors.lastname: Varet
authors.forename: Gilles
authors.initials: G
authors.lastname: Chiocchia
authors.forename: Agnès
authors.initials: A
authors.lastname: Buzyn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis*; D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D020169:Caspases / Q000502:physiology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D007150:Immunohistochemistry; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D011379:Prognosis; D019014:fas Receptor / Q000032:analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D019014:fas Receptor; D020169:Caspases