Mutant nucleophosmin deregulates cell death and myeloid differentiation through excessive caspase-6 and -8 inhibition

• Published in: Blood Vol. 116; no. 17; pp. 3286 - 3296
• Main Authors: Leong, Sai Mun, Tan, Ban Xiong, Bte Ahmad, Baidah, Yan, Tie, Chee, Lai Yuen, Ang, Swee Tin, Tay, Kian Ghee, Koh, Liang Piu, Yeoh, Allen Eng Juh, Koay, Evelyn Siew-Chuan, Mok, Yu-Keung, Lim, Tit Meng
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 28.10.2010; Americain Society of Hematology
• Subjects: Apoptosis; Biological and medical sciences; Caspase 6 - metabolism; Caspase 8 - metabolism; Caspase Inhibitors; Cell Differentiation; Cell Line; Cytoplasm - metabolism; HeLa Cells; Hematologic and hematopoietic diseases; Humans; Medical sciences; Mutation; Myeloid Cells - cytology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Up-Regulation; Peptidases; Nucleophosmin; Hematology; Enzyme; Cell death; Cysteine endopeptidases; Hydrolases; Inhibitor; Mutation; Cell differentiation; Myeloid cell; Apoptosis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-12-256149

In up to one-third of patients with acute myeloid leukemia, a C-terminal frame-shift mutation results in abnormal and abundant cytoplasmic accumulation of the usually nucleoli-bound protein nucleophosmin (NPM), and this is thought to function in cancer pathogenesis. Here, we demonstrate a gain-of-function role for cytoplasmic NPM in the inhibition of caspase signaling. The NPM mutant specifically inhibits the activities of the cell-death proteases, caspase-6 and -8, through direct interaction with their cleaved, active forms, but not the immature procaspases. The cytoplasmic NPM mutant not only affords protection from death ligand-induced cell death but also suppresses caspase-6/-8–mediated myeloid differentiation. Our data hence provide a potential explanation for the myeloid-specific involvement of cytoplasmic NPM in the leukemogenesis of a large subset of acute myeloid leukemia.