Mutant nucleophosmin deregulates cell death and myeloid differentiation through excessive caspase-6 and -8 inhibition.
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.
Leong
Sai Mun
SM
Department of Biological Sciences, National University of Singapore, Singapore.
Tan
Ban Xiong
BX
Bte Ahmad
Baidah
B
Yan
Tie
T
Chee
Lai Yuen
LY
Ang
Swee Tin
ST
Tay
Kian Ghee
KG
Koh
Liang Piu
LP
Yeoh
Allen Eng Juh
AE
Koay
Evelyn Siew-Chuan
ES
Mok
Yu-Keung
YK
Lim
Tit Meng
TM
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
D061945:Caspase Inhibitors; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D053178:Caspase 6; D053181:Caspase 8