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Absence or Low Expression of Fas-Associated Protein with Death Domain in Acute Myeloid Leukemia Cells Predicts Resistance to Chemotherapy and Poor Outcome

¹ 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; ² Centre d’Investigations Cliniques et INSERM ERM 321, Hôpital Saint-Louis, Paris, France; ³ Laboratoire Central d’Hématologie, ⁴ Laboratoire de Cytogénétique, ⁵ Service d’Hématologie Hôtel-Dieu, and ⁶ Service d’Hématologie Adultes, Hôpital Necker-Enfants Malades, Paris, France; and ⁷ Assistance Publique des Hôpitaux de Paris, Paris, France

In acute myeloid leukemia (AML), coexpression of death receptors and ligands of the tumor necrosis factor (TNF) receptor/TNF- 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.

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