title: Extrinsic apoptosis is impeded by direct binding of the APL fusion protein NPM-RAR to TRADD.
abstract: A subset of acute promyelocytic leukemia (APL) cases has been characterized by the t(5;17)(q35;q21) translocation variant, which fuses nucleophosmin (NPM) to retinoic acid receptor α (RARA). The resultant NPM-RAR fusion protein blocks myeloid differentiation and leads to a leukemic phenotype similar to that caused by the t(15;17)(q22;q21) PML-RAR fusion. The contribution of the N-terminal 117 amino acids of NPM contained within NPM-RAR has not been well studied. As a molecular chaperone, NPM interacts with a variety of proteins implicated in leukemogenesis. Therefore, a proteomic analysis was conducted to identify novel NPM-RAR-associated proteins. TNF receptor type I-associated DEATH domain protein (TRADD) was identified as a relevant binding partner for NPM-RAR. This interaction was validated by coprecipitation and colocalization analysis. Biologic assessment found that NPM-RAR expression impaired TNF-induced signaling through TRADD, blunting TNF-mediated activation of caspase-3 (CASP3) and caspase-8 (CASP8), to ultimately block apoptosis.
  
  
  CONCLUSIONS
  This study identifies a novel mechanism through which NPM-RAR affects leukemogenesis.
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Anuja
authors.initials: A
authors.lastname: Chattopadhyay
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Women's Health Integrated Research Center at Inova Health System, Annandale, Virginia.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Hood
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Women's Health Integrated Research Center at Inova Health System, Annandale, Virginia.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Conrads
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. redner@pitt.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Redner
mesh_terms: D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D040901:Proteomics; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction / Q000235:genetics; D053199:TNF Receptor-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*; D014178:Translocation, Genetic / Q000235:genetics
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D053199:TNF Receptor-Associated Death Domain Protein; D000090243:Nucleophosmin; D053148:Caspase 3; D053181:Caspase 8