title: Mutant nucleophosmin deregulates cell death and myeloid differentiation through excessive caspase-6 and -8 inhibition.
abstract: 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.
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore.
authors.forename: Sai Mun
authors.initials: SM
authors.lastname: Leong
authors.forename: Ban Xiong
authors.initials: BX
authors.lastname: Tan
authors.forename: Baidah
authors.initials: B
authors.lastname: Bte Ahmad
authors.forename: Tie
authors.initials: T
authors.lastname: Yan
authors.forename: Lai Yuen
authors.initials: LY
authors.lastname: Chee
authors.forename: Swee Tin
authors.initials: ST
authors.lastname: Ang
authors.forename: Kian Ghee
authors.initials: KG
authors.lastname: Tay
authors.forename: Liang Piu
authors.initials: LP
authors.lastname: Koh
authors.forename: Allen Eng Juh
authors.initials: AE
authors.lastname: Yeoh
authors.forename: Evelyn Siew-Chuan
authors.initials: ES
authors.lastname: Koay
authors.forename: Yu-Keung
authors.initials: YK
authors.lastname: Mok
authors.forename: Tit Meng
authors.initials: TM
authors.lastname: Lim
mesh_terms: D017209:Apoptosis; D053178:Caspase 6 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors; D002454:Cell Differentiation; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D022423:Myeloid Cells / Q000166:cytology*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D000090243:Nucleophosmin; D015854:Up-Regulation
chemical_list: D061945:Caspase Inhibitors; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D053178:Caspase 6; D053181:Caspase 8