Extrinsic apoptosis is impeded by direct binding of the APL fusion protein NPM-RAR to TRADD

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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-RARfusion 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.TNFreceptor type I-associatedDEATHdomain 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.

Original languageEnglish
Pages (from-to)1283-1291
Number of pages9
JournalMolecular Cancer Research
Issue number9
StatePublished - 1 Sep 2014
Externally publishedYes


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