Work

Extrinsic Apoptosis Is Impeded by Direct Binding of the APL Fusion Protein NPM-RAR to TRADD

Year: 2014

Type: article

Abstract: UNLABELLED: 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. IMPLICATIONS: This study identifies a novel mechanism through which NPM-RAR affects leukemogenesis.

Source: Molecular Cancer Research

DOI: 10.1158/1541-7786.mcr-14-0080

Authors: Anuja Chattopadhyay, Brian L. Hood, Thomas P. Conrads, Robert L. Redner

Institutions: University of Pittsburgh, UPMC Hillman Cancer Center, Inova Health System

Language: English

Topic: Retinoids in leukemia and cellular processes

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funder: National Cancer Institute